Burgers medicinal chemistry and drug discovery vol 6 nervous system agents

West Virginia University Morgantown, West Virginia Contents 1 Introduction, 2 2 Clinical Applications, 2 2.1 Current Drugs, 2 2.1.1 Applications of General Adrenergic Agonists, 9 2.1

BURGER'S MEDICINAL

DRUG DISCOVERY

Sixth Edition Volume 6: Nervous System Agents

Edited by Donald j Abraham Department of Medicinal Chemistry

School of Pharmacy Virginia Commonwealth University

Richmond, Virginia

WILEY- INTERSCIENCE

A john Wiley and Sons, Inc., Publication

The University of Iowa

Iowa City, Iowa

Greenwich, Connecticut Joseph Yevich

Pharmaceutical Research Institute Bristol-Myers Squibb Company Wallingford, Connecticut

Kenneth R Scott School of Pharmacy Howard University Washington, DC

7 NARCOTIC ANALGESICS, 329

Jane V Aldrich Sandra C Vigil-Cruz Department of Medicinal Chemistry School of Pharmacy

University of Kansas Lawrence, Kansas

xiii

Psychiatric Genomics, Inc

Department of Gene Discovery

Pharmacology and Toxicology

USC School of Pharmacy

Los Angeles, California

John L Neumeyer Ross J Baldessarini

Harvard Medical School McLean Hospital

Belmont, Massachusetts

Raymond G Booth

School of Pharmacy The University of North Carolina Chapel Hill, North Carolina

Gene G Kinney

Department of Neuroscience Merck Research Laboratories West Point, Pennsylvania

15 DRUGS TO TREAT EATING AND BODY WEIGHT

DISORDERS, 837

Philip A Carpino John R Hadcock

Pfizer Global Research &

Development-Groton Labs Department of Cardiovascular and Metabolic Diseases

Groton, Connecticut

INDEX, 895

CUMULATIVE INDEX, 923

BURGER'S MEDICINAL CHEMISTRY

A N D

West Virginia University

Morgantown, West Virginia

Contents

1 Introduction, 2

2 Clinical Applications, 2 2.1 Current Drugs, 2 2.1.1 Applications of General Adrenergic Agonists, 9

2.1.2 Applications of a,-Agonists, 12 2.1.3 Applications of a,-Agonists, 13 2.1.4 Applications of p-Agonists, 14 2.1.5 Applications of Antiadrenergics, 14 2.1.6 Applications of Nonselective a-

Antagonists, 15 2.1.7 Applications of Selective a,-

Antagonists, 15 2.1.8 Applications of p-Antagonists, 16 2.1.9 Applications of alp-Antagonists, 16 2.1.10 Applications of Agonists/Antagonists,

16 2.2 Absorption, Distribution, Metabolism, and Elimination, 16

2.2.1 Metabolism of Representative Phenylethylamines, 16

2.2.2 Metabolism of Representative Imidazolines and Guanidines, 18 2.2.3 Metabolism of Representative Quinazolines, 19

2.2.4 Metabolism of Representative Aryl- oxypropanolamines, 19

3 Physiology and Pharmacology, 21 3.1 Physiological Significance, 21 3.2 Biosynthesis, Storage, and Release

of Norepinephrine, 22 3.3 Effector Mechanisms

Burger's Medicinal Chemistry and Drug Discovery of Adrenergic Receptors, 25

Sixth Edition, Volume 6: Nervous System Agents 3.4 Characterization of Adrenergic

Edited by Donald J Abraham Receptor Subtypes, 25

ISBN 0-471-27401-1 0 2003 John Wiley & Sons, Inc 4 History, 26

1

Adrenergics and Adrenergic-Blocking Agents

In both their chemical structures and biologi-

cal activities, adrenergics and adrenergic-

blocking agents constitute an extremely var-

ied group of drugs whose clinical utility

includes prescription drugs to treat life-

threatening conditions such as asthma and

hypertension as well as nonprescription med-

ications for minor ailments such as the com-

mon cold This extensive group of drugs in-

cludes synthetic agents as well as chemicals

derived from natural products that have been

used in traditional medicines for centuries

Many adrenergic drugs are among the most

commonly prescribed medications in the

United States, including bronchodilators,

such as albuterol (13) for use in treating

asthma, and antihypertensives, such as ateno-

lo1 (46) and doxazosin (42) Nonprescription

adrenergic drugs include such widely used na-

sal decongestants as pseudoephedrine (5) and

naphazoline (29) Most of these varied drugs

exert their therapeutic effects through action

on adrenoceptors, G-protein-coupled cell sur-

face receptors for the neurotransmitter nor-

epinephrine (noradrenaline, I), and the adre-

nal hormone epinephrine (adrenaline, 2)

(1) norepinephrine, R = H

(2) epinephrine, R = CH3

Adrenoceptors are broadly classified into a-

and preceptors, with each group being further

5.1.5 Imidazolines and Guanidines, 30 5.1.6 Quinazolines, 31

5.1.7 Aryloxypropanolamines, 32

6 Recent Developments, 33 6.1 Selective a,-Adrenoceptor Antagonists, 33 6.2 Selective P,-Agonists, 34

subdivided Identification of subclasses of adre noceptors has been greatly aided by the tools of molecular biology and, to date, six distinct a-ad- renoceptors (a,,, a,,, a,,, ~ Z A , ~ Z B , aZd, and three distinct P-adrenoceptors (PI, P,, P,) have been clearly identified (I), with conflicting evi- dence for a fourth type of /3 (P,) (13) In general the most common clinical applications of a,-ago- nists are as vasoconstrictors employed as nasal decongestants and for raising blood pressure in shock; a,-agonists are employed as antihyper- tensives; a,-antagonists (a-blockers) are vasodi- lators and smooth muscle relaxants employed as antihypertensives and for treating prostatic hy-

perplasia; p-antagonists (p-blockers) are em-

ployed as antihypertensives and for treatingcar- diac arrhythmias; and p-agonists are employed

as bronchodilators The most novel recent ad- vances in adrenergic drug research have been directed toward development of selective p,-ago- nists that have potential applications in treat- ment of diabetes and obesity (4-8)

2 CLINICAL APPLICATIONS

2.1 Current Drugs

U.S Food and Drug Administration (FDA)- approved adrenergic and antiadrenergic drugs currently available in the United States are summarized in Table 1.1, which is organized

in general according to pharmacological mech- anisms of action and alphabetically within those mechanistic classes Structures of the currently employed drugs are given in Tables 1.2-1.6 according to chemical class Drugs in a given mechanistic class often have more than one therapeutic application, and may or may not all be structurally similar Furthermore, drugs from several different mechanistic classes may be employed in a given therapeu-

Table 1.1 Adrenergic and Antiadrenergic Pharmaceuticals

Class and Generic Name Trade Name a Originator Chemical Class Dose bc

various

SmithKline & French Klinge

Phenylethylamine Phenylethylamine Phenylethylamine

5-60 mglday

1 drop 2 X daily 0.1% soln

50-150 mglday for asthma

10-25 mg i.v for hypotension

Wyeth Sterling

Phenylethylamine Phenylethylamine Phenylethylamine

Winthrop Sharpe & Dohme Burroughs Wellcome Oesterreichische Stickstoffwerke Ciba

Phenylethylamine Phenylethylamine Phenylethylamine Phenylethylamine

Imidazoline Imidazoline

Iopidine Alphagan Catapress Wytensin Tenex Aldomet

Aminoimidazoline Aminoimidazoline Aminoimidazoline Arylguanidine Arylguanidine Aromatic amino acid

Table 1.1 (Continued)

Class and Generic Name Trade Namea Originator Chemical Class Dose bc

Proventil, Ventolin Allen & Hanburys Phenylethylamine 12-32 mg/day p.0

Sterling Phenylethylamine

Phenylethylamine Phenylethylamine Phenylethylamine

Yamanouchi

I G Farben Boehringer

Xopenex Alupent, Metaprel

Sepracor Boehringer

Phenylethylamine Phenylethylamine

Maxair Yutopar

Pfizer Philips

Pyridylethylamine Phenylethylamine

Glaxo Draco

Phenylethylamine Phenylethylamine

Hylorel Ismelin reserpine Demser

Cutter Ciba Ciba Merck

Guanidine Guanidine Alkaloid Aromatic amino acid

Angelini-Francesco SmithKline & French Ciba

Ciba

Piperidinlytriazole Haloalkylamine Imidazoline Imidazoline

Pfizer Pfizer

Quinazoline Quinazoline

Yamanouchi Abbott

Phenylethylamine Quinazoline

Zebeta Cartrol, Ocupress Brevibloc

Betaxon Betagan OptiPranolol Lopressor, Toprol-XL Toprol-XL

Corgard Levatol Visken Inderal, Inderal LA

Betapace Timoptic

Coreg Normodyne

Dobutrex Vasodilan

May & Baker ICI

Synthelabo

Merck Otsuka American Hospital Supply Alcon

Warner-Lambert Boehringer

AB Hksle

Squibb Hoechst Sandoz ICI Mead Johnson Frosst

Boehringer Allen & Hanburys

Lilly Philips

Aryloxypropanolamine Aryloxypropanolamine Aryloxypropanolamine

Aryloxypropanolamine Aryloxypropanolamine Aryloxypropanolamine Aryloxypropanolamine Aryloxypropanolamine Aryloxypropanolamine Aryloxypropanolamine

Aryloxypropanolamine Aryloxypropanolamine Aryloxypropanolamine Aryloxypropanolamine Phenylethylamine Aryloxypropanolamine

Aryloxypropanolamine Phenylethylamine

Phenylethylamine Arylpropanolamine

200-1200 mglday

25-150 mglday Hypertension: 10-20 mg orally Glaucoma: 1-2 drops 0.5% soh 2 x daily

1.25-20 mglday

2.5-10 mglday

50-100 pg/kg/min

1 drop 0.5% soln., 2X daily

1-2 drops 0.5% soln., 1-2X daily

1 drop 0.3% soln , 2 x daily

"Not all trade names are listed, particularly for drugs no longer under patent

bAU dose information from Drug Facts a n d Comparisons 2002 (14)

"Not all doses and dosage forms are listed For further information consult reference (14)

Table 1.2 Phenylethylamines (Structures 1-28)

R 4 4' \

C H ~

"Agonist activity unless indicated otherwise

bIndirect activity through release of norepinephrine and reuptake inhibition

"Prodrug

dMixed direct and indirect activity

'Norepinephrine biosynthesis inhibitor

fNet sum of effects of enantiomers

8 Adrenergics and Adrenergic-Blocking Agents Table 1.3 Imidazolines and Guanidines (Structures 29 - 41)

2 Clinical Applications

Table 1.3 (Continued)

"Inhibit release of norepinephrine

tic application; for example, p-blockers, a,-

blockers, and a,-agonists are all employed to

treat hypertension

2.1.1 Applications of General Adrenergic

Agonists The mixed a- and p-agonist norepi-

nephrine (1) has limited clinical application

because of the nonselective nature of its action

in stimulating the entire adrenergic system

In addition to nonselective activity, it is orally

inactive because of rapid first-pass metabo-

lism of the catechol hydroxyls by catechol-0-

methyl-transferase (COMT) and must be ad-

ministered intravenously Rapid metabolism

limits its duration of action to only 1 or 2 min,

even when given by infusion Because its a-ac-

tivity constricts blood vessels and thereby

raises blood pressure, (1) is used to counteract various hypotensive crises and as an adjunct treatment in cardiac arrest where its p-activ- ity stimulates the heart Although it also lacks oral activity because it is a catechol, epineph- rine (2) is far more widely used clinically than

(1) Epinephrine, like norepinephrine, is used

to treat hypotensive crises and, because of its greater p-activity, is used to stimulate the heart in cardiac arrest When administered in- travenously or by inhalation, epinephrine's

&activity makes it useful in relieving bron- choconstriction in asthma Because it has sig- nificant a-activity, epinephrine is also used in topical nasal decongestants Constriction of dilated blood vessels by a-agonists in mucous membranes shrinks the membranes and re-

10 Adrenergics and Adrenergic-Blocking Agents Table 1.4 Quinazolines (Structures 42-44)

duces nasal congestion Dipivefrin (4) is a pro-

drug form of (2), in which the catechol hy-

droxyls are esterified with pivalic acid

Dipivefrin is used to treat open-angle glau-

coma through topical application to the eye

where the drug (4) is hydrolyzed to epineph-

rine (2), which stimulates both a- and P-recep-

tors, resulting in both decreased production

and increased outflow of aqueous humor,

which in turn lowers intraocular pressure

Amphetamine (3) is orally active and,

through an indirect mechanism, causes a gen-

eral activation of the adrenergic nervous sys-

tem Unlike (1) and (2), amphetamine readily

crosses the blood-brain barrier to activate a

number of adrenergic pathways in the central

nervous system (CNS) Amphetamine's CNS

activity is the basis of its clinical utility in

treating attention-deficit disorder, narco-

lepsy, and use as an anorexiant These thera-

peutic areas are treated elsewhere in this

volume

Ephedrine erythro-(5) and pseudoephed-

rine threo-(5) are diastereomers with ephed-

rine, a racemic mixture of the R,S and S,R

stereoisomers, and pseudoephedrine, a race-

mic mixture of R,R and S,S stereoisomers Ephedrine is a natural product isolated from several species of ephedra plants, which were used for centuries in folk medicines in a vari- ety of cultures worldwide (9) Ephedrine has both direct activity on adrenoceptors and indi- rect activity, through causing release of nor- epinephrine from adrenergic nerve terminals Ephedrine is widely used as a nonprescription bronchodilator It has also been used as a va- sopressor and cardiac stimulant Lacking phe- nolic hydroxyls, ephedrine crosses the blood- brain barrier far better than does epinephrine Because of its ability to penetrate the CNS, ephedrine has been used as a stimulant and exhibits side effects related to its action in the brain such as insomnia, irritability, and anxi- ety It suppresses appetite and in high doses can cause euphoria or even hallucinations In the United States the purified chemical ephed- rine is considered a drug and regulated by the FDA However, the dried plant material ma huang is considered by law to be a dietary sup- plement, and not subject to FDA regulation

As a result there are a large number of ma huang-containing herbal remedies and "nu-

2 Clinical Applications 11

Table 1.5 Aryloxypropanolamines (Structures 45-59)

OH Rn-o&NH-

12 Adrenergics and Adrenergic-Blocking Agents

Table 1.5 (Continued)

Plt Pz

triceuticals" on the market whose active in-

gredient is the adrenergic agonist ephedrine

Pseudoephedrine, the threo diastereomer, has

virtually no direct activity on adrenergic re-

ceptors but acts by causing the release of nor-

epinephrine from nerve terminals, which in

turn constricts blood vessels Although it too

crosses the blood-brain barrier, pseudoephed-

rine's lack of direct activity affords fewer CNS

side effects than does ephedrine Pseudo-

ephedrine is widely used as a nasal deconges-

tant and is an ingredient in many nonprescrip-

tion cold remedies

Mephentermine (8) is another general ad-

renergic agonist with both direct and indirect

activity Mephentermine's therapeutic utility

is as a parenteral vasopressor used to treat

hypotension induced by spinal anesthesia or

2 Clinical Applications

Table 1.6 Miscellaneous AdrenergiclAntiadrenergics (Structures 60-62)

H\\\'

0CH3 CH302C = -

O C H ~

0CH3 0CH3

H3C

amide prodrug, hydrolyzed in vivo to (63), an

analog of methoxamine, and a vasoconstrictor

Midodrine is used to treat orthostatic hypo-

tension

Phenylephrine (111, also a selective a-ago-

nist, may be administered parenterally for

severe hypotension or shock but is much more widely employed as a nonprescription nasal decongestant in both oral and topical preparations

The imidazolines naphazoline (29), oxy- metazoline (301, tetrahydozoline (31), and xy- lometazoline (32) are all selective a,-agonists, widely employed as vasoconstrictors in topical nonprescription drugs for treating nasal con- gestion or bloodshot eyes Naphazoline and oxymetazoline are employed in both nasal de- congestants and ophthalmic preparations, whereas tetrahydrozoline is currently mar- keted only for ophthalmic use and xylometa- zoline only as a nasal decongestant

2.1.3 Applications of a,-Agonists Arnino- imidazolines apraclonidine (33) and bri- monidine (34) are selective a,-agonists em- ployed topically in the treatment of glaucoma

Stimulation of a,-receptors in the eye reduces production of aqueous humor and enhances outflow of aqueous humor, thus reducing in- traocular pressure Brimonidine is substan- tially more selective for a,-receptors over a,-

Adrenergics and Adrenergic-Blocking Agents

receptors than is apraclonidine Although both

are applied topically to the eye, measurable

quantities of these drugs are detectable in

plasma, so caution must be employed when

the patient is also taking cardiovascular

agents Structurally related aminoimidazoline

clonidine (35) is a selective a2-agonist taken

orally for treatment of hypertension The anti-

hypertensive actions of clonidine are mediated

through stimulation of a,-adrenoceptors

within the CNS, resulting in an overall decrease

in peripheral sympathetic tone Guanabenz (36)

and guanfacine (37) are ring-opened analogs of

(351, acting by the same mechanism and em-

ployed as centrally acting antihypertensives

Methyldopa (12) is another antihyperten-

sive agent acting as an a,-agonist in the CNS

through its metabolite, a-methyl-norepineph-

rine (65) Methyldopa [the drug is the L-(5')-

stereoisomer] is decarboxylated to a-methyl-

dopamine (64) followed by stereospecific

p-hydroxylation to the (1R,2S) stereoisomer

of a-methylnorepinephrine (65) This stereo-

isomer is an a,-agonist that, like clonidine,

guanabenz, and guanfacine, causes a decrease

in sympathetic output from the CNS

2.1.4 Applications of fi-Agonists Most of

the /3-selective adrenergic agonists, albuterol

(13; salbutamol in Europe), bitolterol (141,

formoterol (15), isoetharine (16), isoprotere- no1 (17), levalbuterol [R-(-)-(1311, metapro- terenol (18), pirbuterol (191, salmeterol (21), and terbutaline (22) are used primarily as bronchodilators in asthma and other constric- tive pulmonary conditions Isoproterenol(17)

is a general P-agonist; and the cardiac stimu- lation caused by its &-activity and its lack of oral activity attributed to first-pass metabo- lism of the catechol ring have led to dimin- ished use in favor of selective p,-agonists Noncatechol-selective P2-agonists, such as al- buterol (13), metaproterenol (181, and ter- butaline (22), are available in oral dosage forms as well as in inhalers All have similar activities and durations of action Pirbuterol (19) is an analog of albuterol, in which the benzene ring has been replaced by a pyridine ring Similar to albuterol, (19) is a selective P2-agonist, currently available only for admin- istration by inhalation Bitolterol(14) is a pro- drug, in which the catechol hydroxyl groups have been converted to 4-methylbenzoic acid esters, providing increased lipid solubility and prolonged duration of action Bitolterol is ad- ministered by inhalation, and the ester groups are hydrolyzed by esterases to liberate the ac- tive catechol drug (66), which is subject to me- tabolism by COMT, although the duration of action of a single dose of the prodrug is up to

8 h, permitting less frequent administration and greater convenience to the patient More recently developed selective &-agonist bron- chodilators are formoterol(l5) and salmeterol (21), which have durations of action of 12 h or more Terbutaline (221, in addition to its use

as a bronchodilator, has also been used for halting the contractions of premature labor Ritodrine (20) is a selective P2-agonist that is used exclusively for relaxing uterine muscle and inhibiting the contractions of premature labor

2.1.5 Applications of Antiadrenergics Gua- nadrel (38) and guanethidine (39) are orally active antihypertensives, which are taken up into adrenergic neurons, where they bind to the storage vesicles and prevent release of neurotransmitter in response to a neuronal impulse, which results in generalized decrease

in sympathetic tone These drugs are available but seldom used

2 Clinical Applications

Reserpine (60) is an old and historically im-

portant drug that affects the storage and re-

lease of norepinephrine Reserpine is one of

several indole alkaloids isolated from the roots

of Rauwolfia serpentina, a plant whose roots

were used in India for centuries as a remedy

for snakebites and as a sedative Reserpine

acts to deplete the adrenergic neurons of their

stores of norepinephrine by inhibiting the ac-

tive transport Mg-ATPase responsible for se-

questering norepinephrine and dopamine

within the storage vesicles Monoamine oxi-

dase (MAO) destroys the norepinephrine and

dopamine that are not sequestered in vesicles

As a result the storage vesicles contain little

neurotransmitter; adrenergic transmission is

dramatically inhibited; and sympathetic tone

is decreased, thus leading to vasodilation

Agents with fewer side effects have largely re-

placed reserpine in clinical use

Metyrosine (23, a-methyl-L-tyrosine), a

norepinephrine biosynthesis inhibitor, is in

limited clinical use to help control hyperten-

sive episodes and other symptoms of catechol-

amine overproduction in patients with the

rare adrenal tumor pheochromocytoma (10)

Metyrosine, a competitive inhibitor of ty-

rosine hydroxylase, inhibits the production of

catecholamines by the tumor Although mety-

rosine is useful in treating hypertension

caused by excess catecholamine biosynthesis

in pheochromocytoma tumors, it is not useful for treating essential hypertension

2.1.6 Applications of Nonselective a-An- tagonists Because antagonism of a,-adreno- ceptors in the peripheral vascular smooth muscle leads to vasodilation and a decrease in blood pressure attributed to a lowering of pe- ripheral resistance, alpha-blockers have been employed as antihypertensives for decades However, nonselective a-blockers such as phe- noxybenzamine (62), phentolamine (40), and tolazoline can also increase sympathetic out- put through blockade of inhibitory presynap- tic a,-adrenoceptors, resulting in an increase

in circulating norepinephrine, which causes reflex tachycardia Thus the use of these agents in treating most forms of hypertension has been discontinued and replaced by use of selective a,-antagonists discussed below Cur- rent clinical use of the nonselective agents (40), (41), and (62) is primarily treatment of hypertension induced by pheochromocytoma,

a tumor of the adrenal medulla, which se- cretes large amounts of epinephrine and nor- epinephrine into the circulation Dapiprazole (61) is an ophthalmic nonselective a-antago- nist applied topically to reverse mydriasis in- duced by other drugs and is not used to treat hypertension

2.1.7 Applications of Selective a,-Antago- nists Quinazoline-selective a,-blockers dox- azosin (42), prazosin (43), and terazosin (44) have replaced the nonselective a-antagonists

in clinical use as antihypertensives Their abil- ity to dilate peripheral vasculature has also made these drugs useful in treating Raynaud's syndrome The a,-selective agents have a fa- vorable effect on lipid profiles and decrease low density lipoproteins (LDL) and triglycer- ides, and increase high density lipoproteins

(HDL)

Contraction of the smooth muscle of the prostate gland, prostatic urethra, and bladder neck is also mediated by a,-adrenoceptors, with a,, being predominant, and blockade of these receptors relaxes the tissue For this rea- son the quinazoline a,-antagonists doxazosin (42), prazosin ( 4 9 , and terazosin (44) have also found use in treatment of benign pros- tatic hyperplasia (BPH) However, prazosin,

Adrenergics and Adrenergic-Blocking Agents

doxazosin, and terazosin show no significant

selectivity for any of the three known a,-adre-

noceptor subtypes, a,,, a,,, and a,, (11) The

structurally unrelated phenylethylamine a,-

antagonist tamsulosin (24) is many fold more

selective for a,,-receptors than for the other

a,-adrencoceptors Tamsulosin is employed

only for treatment of BPH, given that it has

little effect on the a,,- and a,,-adrenoceptors,

which predominate in the vascular bed (12)

and have little effect on blood pressure (13)

2.1.8 Applications of &Antagonists p-An-

tagonists are among the most widely employed

antihypertensives and are also considered the

first-line treatment for glaucoma There are

16 p-blockers listed in Table 1.1 and 15 of

them are in the chemical class of aryloxypro-

panolamines Only sotalol(25) is a phenyleth-

ylamine Acebutolol (451, atenolol (46), biso-

pro101 (481, metoprolol (53), nadolol (54),

penbutolol (551, pindolol (561, and proprano-

lo1 (57) are used to treat hypertension but not

glaucoma Betaxolol (471, carte0101 (49), and

timolol(58) are used both systemically to treat

hypertension and topically to treat glaucoma

Levobetaxolol [S-(-)-(47)], levobunolol (51),

and metipranolol (52) are employed only in

treating glaucoma Betaxolol (racemic 47) is

available in both oral and ophthalmic dosage

forms for treating hypertension and glau-

coma, respectively, but levobetaxolol, the en-

antiomerically pure S-(-)-stereoisomer is cur-

rently available only in an ophthalmic dosage

form Esmolol (50) is a very short acting

p-blocker administered intravenously for

acute control of hypertension or certain su-

praventricular arrhythmias during surgery

Sotalol(25) is a nonselective p-blocker used to

treat ventricular and supraventricular ar-

rhythmias not employed as an antihyperten-

sive or antiglaucoma agent P-Antagonists

must be used with caution in patients with

asthma and other reactive pulmonary diseases

because blockade of P,-adrenoceptors may ex-

acerbate the lung condition Even the agents

listed as being &-selective have some level of

p,-blocking activity at higher therapeutic

doses Betaxolol is the most p,-selective of the

currently available agents

2.1.9 Applications of dj3-Antagonists Car- vedilol (591, an aryloxypropanolamine, has both a- and p-antagonist properties and is used both as an antihypertensive and to treat cardiac failure Both enantiomers have selec- tive a,-antagonist properties but most of the p-antagonism is attributable to the S-(-) iso- mer Labetalol(26) is also an antihypertensive with both selective a,-antagonist properties and nonselective p-antagonism Labetalol is

an older drug than carvedilol and is not as potent as carvedilol, particularly as a p-antag- onist

2.1 I 0 Applications of Agonists/Antago- nists Dobutamine (27) is a positive inotropic agent administered intravenously for conges- tive heart failure The (+)-isomer has both a

and p agonist effects, whereas the (-)-isomer

is an a-antagonist but a P-agonist like the en- antiomer The p-stirnulatory effects predomi- nate as the a-effects cancel As a catechol it has no oral activity and even given intrave- nously has a half-life of only 2 min Isoxsu- prine (28) is an agent with a-antagonist and P-agonist properties, which has been used for peripheral and cerebral vascular insufficiency and for inhibition of premature labor Isoxsu- prine is seldom used any more

2.2 Absorption, Distribution, Metabolism, and Elimination

Because of the large numbers of chemicals act- ing as either adrenergics or adrenergic-block- ing drugs, only representative examples will

be given and limited to metabolites identified

in humans Because drugs with similar struc- tures are often metabolized by similar routes, the examples chosen are representative of each structural class Although it contains no structural details of metabolic pathways,

Drug Facts and Comparisons (14) is an out- standing comprehensive compilation of phar- macokinetic parameters such as absorption, duration of action, and routes of elimination for drugs approved by the FDA for use in the United States

2.2.1 Metabolism of Representative Phenyl- ethylamines Norepinephrine (1) and epi- nephrine (2) are both substrates for MAO,

2 Clinical Applications

which oxidatively deaminates the side chain of

either to form the same product DOPGAL

(67), and for catechol-0-methyltransferase

(COMT), which methylates the 3'-phenolic

OH of each to form (68) Metabolite (68) is

subsequently oxidized by MA0 to form alde-

hyde (69), and aldehyde (68) may be methyl-

ated by COMT to also form (69) This alde-

hyde may then be either oxidized by aldehyde

dehydrogenase (AD) to (70) or reduced by al-

dehyde reductase to alcohol (71) Alternate

routes to (70) and (71) from (67) are also

shown Several of these metabolites are ex-

creted in the urine as sulfate and glucuronide

conjugates (15) As previously mentioned, nei-

ther (1) nor (2) is orally active because of ex-

tensive first-pass metabolism by COMT, and

both have short durations of action because of

rapid metabolic deactivation by the routes

shown Any catechol-containing drug will also likely be subject to metabolism by COMT Ephedrine (51, a close structural analog of

(2), having no substituents on the phenyl ring,

is well absorbed after an oral dose and over half the dose is eliminated unchanged in the urine The remainder of the dose is largely desmethylephedrine (72), deamination prod- uct (73), and small amounts of benzoic acid and its conjugates (16) No aromatic ring-hy-

droxylation products were detected This is in marked contrast to the case with amphet- amine (3), in which ring-hydroxylated prod- ucts are major metabolites

Albuterol(13) is not subject to metabolism

by COMT and is orally active but does have a 4'- OH group subject to conjugation The ma- jor metabolite of albuterol (13) is the 4'-0- sulfate (74) (17) The sulfation reaction is ste-

Adrenergics and Adrenergic-Blocking Agents

reoselective for the active R-(-)-isomer (18-

201, resulting in higher plasma levels of the

less active S-(+)-isomer after oral administra-

tion or swallowing of inhaled dosages

Tamsulosin (24) is metabolized by CYP3A4

to both the phenolic oxidation product (75)

and deaminated metabolite (76) and their con-

jugation products (21-23) The other products

generated from the remainder of the drug

molecule during formation of (76) were not

explicitly identified Tamsulosin is well ab-

sorbed orally and extensively metabolized

Less than 10% excreted unchanged in urine

2.2.2 Metabolism of Representative Imida-

zolines and Cuanidines In humans, clonidine

(35) is excreted about 50% unchanged in the

urine and the remainder oxidized by the liver

on both the phenyl ring and imidazoline ring

to (771, (781, and (79) Oxidation of the imida- zoline ring presumably leads to the ring- opened derivatives (80) and (81) All metabo- lites are inactive but do not appear to be further conjugated

In contrast, less than 2% of guanabenz (36), a ring-opened analog of (351, is excreted unchanged in the urine (24) The major me- tabolite (35%) is the 4-hydroqdated com- pound (82) and its conjugates, whereas guana- benz-N-glucuronide accounts for about 6% Also identified were 2,6-dichlorobenzyl alco- hol (83) (as conjugates) and the 2-isomer of

2 Clinical Applications

guanabenz About 15 other trace metabolites

were detected by chromatography but not

identified

2.2.3 Metabolism of Representative Quina-

zolines Terazosin (46) is completely absorbed,

with little or no first-pass metabolism, and about 38% of administered terazosin is elimi- nated unchanged in urine and feces The re- mainder is metabolized by hydrolysis of the amide bond to afford (84) and by O-demethyl- ation to form the 6- and 7-0-demethyl metab- olites (85) and (86), respectively (25) Diamine (87) has also been identified as a minor metab- olite of terazosin, probably arising from oxida- tion and hydrolysis of the piperazine ring, al- though the intermediate products have not been identified

Doxazosin (42) is well absorbed, with 60% bioavailability, but only about 5% is ex- creted unchanged The major routes of me- tabolism are, like terazosin, 6- and 7-0- demethylation t o afford (88) and (891, respectively (26) Hydroxylation a t 6' and 7',

to form (90) and (91), forms the other two identified metabolites

2.2.4 Metabolism of Representative Aryl- oxypropanolamines Propranolol ( 5 7 ) , the first successful p-blocker, is also the most li- pophilic, with an octanol/water partition coef- ficient of 20.2 (27), and is extensively metabo- lized At least 20 metabolites of propranolol have been demonstrated (28), only a few of which are shown The 4'-hydroxy metabolite (92) is equipotent with the parent compound (29) CYP2D6 is responsible for the 4'-hy- droxylation and CYPlA2 for oxidative re- moval of the isopropyl group from the nitro- gen to form (93) (30) The metabolites as well

as the parent drug are extensively conjugated

CH20H

+ conjugates + Z-isomer of (36)

C1

20 Adrenergics and Adrenergic-Blocking Agents

3 Physiology and Pharmacology 21

@ O"

'OZH+ many conjugates

as sulfates and glucuronides The high lipophi-

licity of propranolol provides ready passage

across the blood-brain barrier and leads to the

significant CNS effects of propranolol(27)

On the other hand, atenolol (461, with an

octanollbuffer partition coefficient of 0.02

(27), does not cross the blood-brain barrier to

any significant extent and is eliminated al-

most entirely as the unchanged parent drug in

the urine and feces Very small amounts of

hydroxylated metabolite (94) and its conju-

gates have been identified (31), but well over

90% of atenolol is eliminated unchanged

Metoprolol(53) is cleared principally by he-

patic metabolism and is only 50% bioavailable

because of extensive first-pass metabolism

The major metabolite (65%) is the carboxylic

acid (951, produced by CYP2D6 O-demethyl-

ation followed by further oxidation (32-34)

Benzylic oxidation CYP2D6 forms an active

metabolite (961, which retains beta-blocking

activity (35) The N-dealkylated product is a

minor metabolite

3 PHYSIOLOGY AND PHARMACOLOGY

The physiology and pharmacology of adrener-

gic and adrenergic-blocking drugs are well

covered in standard pharmacology textbooks

(36,371

3.1 Physiological Significance

Adrenergic and adrenergic-blocking drugs act

on effector cells through receptors that are

normally activated by the neurotransmitter norepinephrine (1, noradrenaline), or they may act on the neurons that release the neu-

rotransmitter The term adrenergic stems

from the discovery early in the twentieth cen- tury that administration of the adrenal med- ullar hormone adrenaline (epinephrine) had specific effects on selected organs and tissues similar to the effects produced by stimulation

of the sympathetic nervous system, which was

Adrenergics and Adrenergic-Blocking Agents

(96) active

originally defined anatomically (38) Today

the terms adrenergic nervous system and sym-

pathetic nervous system are generally used in-

terchangeably The sympathetic nervous sys-

tem is a division of the autonomic nervous

system, which innervates organs such as the

heart, lungs, blood vessels, glands, and smooth

muscle in various tissues and regulates func-

tions not normally under voluntary control

The effects of the sympathetic stimulation on

a few organs and tissues of particular rele-

vance to current pharmaceutical interven-

tions are shown in Table 1.7 (39,40) Excellent

overviews of the adrenergic nervous system

and its role in control of human physiology are

provided in Katzung (39) and Hoffman and

Palmer (40)

3.2 Biosynthesis, Storage, and Release

of Norepinephrine

Biosynthesis of norepinephrine takes place

within adrenergic neurons near the terminus

of the axon near the junction with the effector cell The amino acid L-tyrosine (97) is actively transported into the neuron cell (411, where the cytoplasmic enzyme tyrosine hydroxylase (tyrosine-3-monooxygenase) oxidizes the 3'-

position to form the catechol-amino-acid L- dopa (98) in the rate-limiting step in norepi-

nephrine biosynthesis (42) L-Dopa is decarboxylated to dopamine (99) by aromatic-

L-amino acid decarboxylase, another cytoplas- mic enzyme Aromatic-L-amino acid decarboxyl- ase is more commonly known as dopa decarboxylase Doparnine is then taken up by active transport into storage vesicles or granules located near the terminus of the adrenergic neu- ron Within these vesicles, the enzyme dopa- mine P-hydroxylase stereospecifically intro- duces a hydroxyl group in the R absolute configuration on the carbon atom beta to the amino group to generate the neurotransmitter norepinephrine (1) Norepinephrine is stored in the vesicles in a 4:l complex, with adenosine

3 Physiology and Pharmacology 23

Table 1.7 Selected Tissue Response to Adrenergic Stimulation

Tissue Principal Adrenergic Receptor Effect

Heart PI (minor Pz, P3) Increased rate and force

Blood vessels

Eye

Radial muscle, iris a1 Contraction (pupilary dilation)

Kidney

minor a1 Decreased renin secretion

triphosphate (ATP) in such quantities that each

vesicle in a peripheral adrenergic neuron con-

tains between 6000 and 15,000 molecules of nor-

epinephrine (43) The pathway for epinephrine

(2) biosynthesis in the adrenal medulla is the

same, with the additional step of conversion of

(1) to (2) by phenylethanolamine-N-methyl-

transferase

Norepinephrine remains in the vesicles un-

til it is released into the synapse during signal

transduction A wave of depolarization reach-

ing the terminus of an adrenergic neuron trig-

gers the transient opening of voltage-depen-

dent calcium channels, causing an influx of

calcium ions This influx of calcium ions trig-

gers fusion of the storage vesicles with the

neuronal cell membrane, spilling the norepi-

nephrine and other contents of the vesicles

into the synapse through exocytosis A sum-

mary view of the events involved in norepi-

nephrine biosynthesis, release, and fate is given in Fig 1.1 After release, norepinephrine diffuses through the intercellular space to bind reversibly to adrenergic receptors (alpha

or beta) on the effector cell, triggering a bio- chemical cascade that results in a physiologic response by the effector cell In addition to the receptors on effector cells, there are also adre- noreceptors that respond to norepinephrine (a2-receptors) or epinephrine (P2-receptors)

on the presynaptic neuron, which modulate the release of additional neurotransmitter into the synapse Activation of presynaptic a,-

adrenoceptors by (1) inhibits the release of ad- ditional (I), whereas stimulation of presynap- tic P,-adrenoceptors by (2) enhances the release of (I), thus increasing overall sympa- thetic activation Removal of norepinephrine from the synapse is accomplished by two mechanisms, reuptake and metabolism, to in-

3 Physiology and Pharmacology

active compounds The most important of

these mechanisms is transmitter recycling

through active transport uptake into the pre-

synaptic neuron This process, called up-

take-1, is efficient and, in some tissues, up to

95% of released norepinephrine is removed

from the synapse by this mechanism (44) Part

of the norepinephrine taken into the presyn-

aptic neuron by uptake-1 is metabolized by

MA0 through the same processes discussed

earlier under norepinephrine metabolism, but

most is sequestered in the storage vesicles to

be used again as neurotransmitter This up-

take mechanism is not specific for (1) and a

number of drugs are substrates for the uptake

mechanism and others inhibit reuptake, lead-

ing to increased adrenergic stimulation A less

efficient uptake process, uptakeS, operates in

a variety of other cell types but only in the

presence of high concentrations of norepi-

nephrine That portion of released norepi-

nephrine that escapes uptake-1 diffuses out of

the synapse and is metabolized in extraneuro-

nal sites by COMT MA0 present at extraneu-

ronal sites, principally the liver and blood

platelets, also metabolizes norepinephrine

3.3 Effector Mechanisms

of Adrenergic Receptors

Adrenoceptors are proteins embedded in the

cell membrane that are coupled through a G-

protein to effector mechanisms that translate

conformational changes caused by activation

of the receptor into a biochemical event within

the cell All of the P-adrenoceptors are coupled

through specific G-proteins (G,) to the activa-

tion of adenylyl cyclase (45) When the recep-

tor is stimulated by an agonist, adenylyl cy-

clase is activated to catalyze conversion of

ATP to cyclic-adenosine monophosphate

(CAMP), which diffuses through the cell for at

least short distances to modulate biochemical

events remote from the synaptic cleft Modu-

lation of biochemical events by CAMP includes

a phosphorylation cascade of other proteins

CAMP is rapidly deactivated by hydrolysis of

the phosphodiester bond by the enzyme phos-

phodiesterase The a,-receptor may use more

than one effector system, depending on the

location of the receptor; however, to date the

best understood effector system of the a,-re-

ceptor appears to be similar to that of the p-re-

ceptors, except that linkage through a G-pro- tein (G,) leads to inhibition of adenylyl cyclase instead of activation

The a,-adrenoreceptor, on the other hand,

is linked through yet another G-protein to a complex series of events involving hydrolysis

of polyphosphatidylinositol (46) The first event set in motion by activation of the a,- receptor is activation of the enzyme phospho- lipase C, which catalyzes the hydrolysis of

phosphatidylinositol-4,5-biphosphate (PIP,) This hydrolysis yields two products, each of which has biologic activity as second messen- gers of the a,-receptor These are 1,2-diacyl- glycerol (DAG) and inositol-1,4,5-triphos- phate (IP,) IP, causes the release of calcium ions from intracellular storage sites in the en- doplasmic reticulum, resulting in an increase

in free intracellular calcium levels Increased free intracellular calcium is correlated with smooth muscle contraction DAG activates cy- tosolic protein kinase C, which may induce slowly developing contractions of vascular smooth muscle The end result of a complex series of protein interactions triggered by ag- onist binding to the a,-adrenoceptor includes increased intracellular free calcium, which leads to smooth muscle contraction Because smooth muscles of the wall of the peripheral vascular bed are innervated by a,-receptors, stimulation leads to vascular constriction and

an increase in blood pressure

3.4 Characterization of Adrenergic Receptor Subtypes

The discovery of subclasses of adrenergic re- ceptors and the ability of relatively small mol- ecule drugs to stimulate differentially or block these receptors represented a major advance

in several areas of pharmacotherapeutics An

excellent review of the development of adreno- ceptor classifications is available in Hiebel et

al (47)

The adrenoceptors, both alpha and beta, are members of a receptor superfamily of membrane-spanning proteins, including mus- carine, serotonin, and dopamine receptors, that are coupled to intracellular GTP-binding proteins (G-proteins), which determine the cellular response to receptor activation (48) -

All G-protein-coupled receptors exhibit a common motif of a single polypeptide chain

Adrenergics and Adrenergic-Blocking Agents

that is looped back and forth through the cell

membrane seven times, with an extracellular

N-terminus and intracellular C-terminus

One of the most thoroughly studied of these

receptors is the human P,-adrenoreceptor

(49) The seven transmembrane domains,

TMD1-TMD7, are composed primarily of li-

pophilic amino acids arranged in a-helices

connected by regions of hydrophilic amino ac-

ids The hydrophilic regions form loops on the

intracellular and extracellular faces of the

membrane In all of the adrenoceptors the ag-

onistlantagonist recognition site is located

within the membrane-bound portion of the re-

ceptor This binding site is within a pocket

formed by the membrane-spanning regions of

the peptide All of the adrenoceptors are cou-

pled to their G-protein through reversible

binding interactions with the third intracellu-

lar loop of the receptor protein

Binding studies with selectively mutated

P,-receptors have provided strong evidence

for binding interactions between agonist func-

tional groups and specific residues in the

transmembrane domains of adrenoceptors

(50-52) Such studies indicate that Asp,,, in

transmembrane domain 3 (TMD3) of the P,-

receptor is the acidic residue that forms a

bond, presumably ionic or a salt bridge, with

the positively charged amino group of cate-

cholamine agonists An aspartic acid residue is

also found in a comparable position in all of

the other adrenoceptors as well as other

known G-protein-coupled receptors that bind

substrates having positively charged nitro-

gens in their structures Elegant studies with

mutated receptors and analogs of isoprotere-

no1 demonstrated that Ser,,, and Ser,,, of

TMD5 are the residues that form hydrogen

bonds with the catechol hydroxyls of &-ago-

nists Furthermore, the evidence indicates

that Ser,,, interacts with the meta hydroxyl

group of the ligand, whereas Ser,,, interacts

specifically with the para hydroxyl group

Serine residues are found in corresponding po-

sitions in the fifth transmembrane domain of

the other known adrenoceptors Evidence in-

dicates that the phenylalanine residue of

TMD6 is also involved in ligand-receptor

bonding with the catechol ring Structural dif-

ferences exist among the various adrenocep-

tors with regard to their primary structure,

including the actual peptide sequence and length Each of the adrenoceptors is encoded

on a distinct gene, and this information was considered crucial to the proof that each adre- noreceptor is indeed distinct, although re- lated The amino acids that make up the seven transmembrane regions are highly conserved among the various adrenoreceptors, but the hydrophilic portions are quite variable The largest differences occur in the third intracel- lular loop connecting TMD5 and TMD6, which

is the site of linkage between the receptor and its associated G-protein Sequences and bind- ing specificities have been reported for numer- ous a- and P-adrenoceptor subtypes (47, 53- 56) For purposes of drug design and therapeutic targeting, the most critical recep- tors are the a,, on prostate smooth muscle, a,, on vascular smooth muscle and in the kid- ney, a, in the CNS, P, in heart, P, in bronchial smooth muscle, and p, in adipose tissue

4 HISTORY

In 1895 Oliver and Schafer reported (57) that adrenal gland extracts caused vasoconstric- tion and dramatic increases in blood pressure Shortly thereafter various preparations of crude adrenal extracts were being marketed largely to staunch bleeding from cuts and abrasions In 1899 Abel reported (58) isolation

of a partially purified sample of the active con- stituent (2), which he named epinephrine Shortly thereafter von Fiirth (59) employed an alternative procedure to isolate another im- pure sample of (2), which he named suprare- nin, claiming it to be a different substance than that isolated by Abel The pure hormone (2) was finally obtained in 1901 by both Taka- mine (60) and Aldrich (61) Takamine gave (2) yet a third name, adrenalin Although the chemical structure was still not definitively known, a pure preparation of (2) was first marketed by Parke, Davis & Co under the trade name Adrenaline (62, 63) Adrenaline eventually became the generic name employed outside the United States, whereas epineph- rine became the U.S approved name By 1903 Pauly (64) had demonstrated that "adrena- line" was levorotatory and proposed two pos- sible structures consistent with the available

4 History

data The structure of racemic (2) was conclu-

sively proved through nearly simultaneous

synthesis by Stolz at Farbwerke Hoechst (65)

and Dakin at the University of Leeds (66), but

it had only one half the activity of the natural

levorotatory isomer (67) The racemate was

resolved by Flacher in 1908 (68)

The earliest major clinical application of (2)

was the report in 1900 (69) of the utility of

injected adrenal extracts in treating asthma

attacks, followed in 1903 by a report (70) of the

use of purified (2) for the same purpose In-

jected epinephrine rapidly became the stan-

dard therapy for treatment of acute asthma

attacks A nasal spray containing epinephrine

was available by 1911 and administration

through an inhaler was reported in 1929 Also,

early in the 1900s Hoechst employed the vaso-

constrictor properties of epinephrine to pro-

long the duration of action of their newly de-

veloped local anesthetic procaine (63)

It had been recognized early on (71) that

there were similarities between the effects of

administration adrenal gland extracts and -

stimulation of the sympathetic nervous sys-

tem Elliot (72) suggested that adrenaline

might be released by sympathetic nerve stim-

ulation and over the years the term adrenergic

nerves became effectively synonymous with

sympathetic nerves In 1910 Barger and Dale

(73) reported a detailed structure-activity re-

lationship study of epinephrine analogs and

introduced the term sympathomimetic for

chemicals that mimicked the effects of sympa-

thetic nerve stimulation, but they also noted

some important differences between the ef-

fects of administered adrenaline and stimula-

tion of sympathetic nerves It was not until

1946 that von Euler demonstrated that the

actual neurotransmitter released at the termi-

nus of sympathetic neurons was norepineph-

rine (1) rather than epinephrine (2) (74) In

1947 compound (17), the N-isopropyl analog

of (1) and (21, was reported to possess bron-

chodilating effects similar to those of (2) but

lacking its dangerous pressor effects In 1951

(17) was introduced into clinical use as isopro-

terenol (isoprenaline) and became the drug of

choice for treating asthma for two decades

In the 1950s, dichloroisoprotereno1 (DCI,

loo), a derivative of isoproterenol, in which

the catechol hydroxyls had been replaced by

chlorines, was discovered to be a P-antagonist that blocked the effects of sympathomimetic amines on bronchodilation, uterine relax- ation, and heart stimulation (75) Although DCI had no clinical utility, replacement of the 3,4-dichloro substituents with a carbon bridge

to form a naphthylethanolamine derivative did afford a clinical candidate, pronethalol (1011, introduced in 1962 only to be with- drawn in 1963 because of tumor induction in animal tests

Shortly thereafter, a major innovation was introduced when it was discovered that an oxymethylene bridge, OCH,, could be intro- duced into the arylethanolamine structure of pronethalol to afford propranolol(57), an ary- loxypropanolamine and the first clinically suc- cessful P-blocker

To clarify some of the puzzling differential effects of sympathomimetic drugs on various tissues, in 1948 Ahlquist (76) introduced the concept of two distinct types of adrenergic re- ceptors as defined by their responses to (11, (2), and (17), which he called alpha receptors and beta receptors Alpha receptors were de- fined as those that responded in rank order of agonist potency as (2) > (1) >> (17) Beta re- ceptors were defined as those responding in potency order of (17) > (2) > (1) Subse- quently, P-receptors were further divided into PI-receptors, located primarily in cardiac tis- sue, and &-adrenoceptors, located in smooth muscle and other tissues, given that (1) and (2) are approximately equipotent at cardiac

Adrenergics and Adrenergic-Blocking Agents

P-receptors, although (2) is 10 to 50 times

more potent than (1) at most smooth muscle

P-receptors (77) Alpha receptors were also

subdivided into a, (postsynaptic) and a, (pre-

synaptic) adrenoceptors (78) Development of

selective agonists and antagonists for these

various adrenoceptors has been thoroughly re-

viewed in Ruff010 et al (79)

5 STRUCTURE-ACTIVITY RELATIONSHIPS

Comprehensive reviews of the structure-activ-

ity relationships (SAR) of agonists and antag-

onists of a-adrenoceptors (80) and P-adreno-

ceptors (81) are available, which thoroughly

cover developments through the late 1980s

Only summaries of these structure-activity re-

lationships are provided here

5.1 Phenylethylamine Agonists

The structures of the phenylethylamine ad-

renergic agonists were summarized in Table

1.2 Agents of this type have been extensively

studied over the years since the discovery of

the naturally occurring prototypes, epineph-

rine and norepinephrine, and the structural

requirements, and tolerances for substitu-

tions at each of the indicated positions have

been well established and reviewed (79,82) In

general, a primary or secondary aliphatic

amine separated by two carbons from a substi-

tuted benzene ring is minimally required for

high agonist activity in this class Tertiary or

quaternary amines have little activity Be-

cause of the basic amino groups, pK, values

range from about 8.5 to 10, and all of these

agents are highly positively charged at physi-

ologic pH Most agents in this class have a

hydroxyl group on C-1 of the side chain, P to

the amine, as in epinephrine and norepineph-

rine Given these features in common, the na-

ture of the other substituents determines re- ceptor selectivity and duration of action

5.1.1 R' Substitution on the Amino Nitrogen

As R1 is increased in size from hydrogen in

norepinephrine to methyl in epinephrine to isopropyl in isoproterenol, activity at a-recep- tors decreases and activity at P-receptors in- creases Activity at both a- and P-receptors is maximal when R1 is methyl as in epinephrine, but a-agonist activity is dramatically de- creased when R1 is larger than methyl and is negligible when R1 is isopropyl as in (17), leav- ing only P-activity Presumably, the P-recep- tor has a large lipophilic binding pocket adja- cent to the amine-binding aspartic acid residue, which is absent in the a-receptor As R1 becomes larger than butyl, affinity for a,-

receptors returns, but not intrinsic activity, which means large lipophilic groups can afford compounds with a,-blocking activity [e.g., tamsulosin (24) and labetalol (26)l Tarnsulo- sin (24) is more selective for a,,, the a,-adre- noceptor subtype found in the prostate gland, over those found in vascular tissue In addi- tion, the N-substituent can also provide selec- tivity for different P-receptors, with a t-butyl group affording selectivity for &-receptors For example, with all other features of the molecules being constant, (66) [the active metabolite of prodrug bitolterol (1411 is a se- lective P,-agonist, whereas (17) is a general P-agonist When considering its use as a bron- chodilator, it must be recognized that a gen- eral P-agonist such as (17) has undesirable cardiac stimulatory properties (because of its

&-activity) that are greatly diminished in a selective P,-agonist

5.1.2 RZ Substitution a to the Basic Nitro- gen, Carbon-2 Small alkyl groups, methyl or ethyl, may be present on the carbon adjacent

to the amino nitrogen Such substitution slows metabolism by MA0 but has little over- all effect on duration of action of catechols be- cause they remain substrates for COMT Re-

sistance to MA0 activity is more important

in noncatechol indirect-acting phenylethyl- amines An ethyl group in this position dimin- ishes a-activity far more than P-activity, and is present in isoetharine (16) Substitution on this carbon introduces an asymmetric center,

5 Structure-Activity Relationships

producing pairs of diastereomers when an OH

group is present on C-1 These stereoisomers

can have significantly different biologic and

chemical properties For example, maximal

direct activity in the stereoisomers of a-meth-

ylnorepinephrine resides in the erythro ste-

reoisomer (65), with the (1R,2S) absolute con-

figuration (83), which is the active metabolite

of the prodrug methyldopa (12) (84) The con-

figuration of C-2 has a great influence on re-

ceptor binding because the (1R,2R) diaste-

reomer of a-methylnorepinephrine has

primarily indirect activity, even though the ab-

solute configuration of the hydroxyl-bearing C-1

is the same as that in norepinephrine In

addition, with respect to a-activity, this addi-

tional methyl group also makes the direct-acting

(1R,2S) isomer of a-methylnorepinephrine se-

lective for a,-adrenoceptors over a,-adrenocep-

tors, affording the central antihypertensive

properties of methyldopa

5.1.3 R 3 Substitution on Carbon-1 In the

phenylethyamine series, a hydroxyl group at

this position in the R absolute configuration is

preferred for maximum direct agonist activity

on both a- and p-adrenoceptors If a hydroxyl

is present in the S absolute configuration, the

activity is generally the same as that of the

corresponding chemical with no substituent

This is the basis for the well-known Easson-

Stedman hypothesis of three-point attachment

of phenylethanolamines to adrencoceptors

through stereospecific bonding interactions

with the basic amine, hydroxyl group, and ar-

omatic substituents (85) A comprehesive and

excellent review of the stereochemistry of ad-

renergic drug-receptor interactions was writ-

ten by Ruff010 (86)

An example of a phenethylamine agonist

lacking an OH group on C-1 is dobutamine

(27), which has activity on both a- and p-re-

ceptors but, because of some unusual proper-

ties of the c h i d center on R1, the bulky nitro-

gen substituent, the overall pharmacologic

response is that of a selective PI-agonist (87)

he (-)-isomer of dobutamine is an a,-agonist

and vasopressor The (+)-isomer is a n a,-

antagonist; thus, when the racemate is used

clinically, the a-effects of the enantiomers ef-

fectively cancel, leaving the p-effects to pre-

dominate The stereochemistry of the methyl

substituent does not affect the ability of the drug to bind to the a,-receptor but does affect the ability of the molecule to activate the re- ceptor; that is, the stereochemistry of the methyl group affects intrinsic activity but not affinity Because both stereoisomers are p-agonists, with the (+)-isomer about 10 times as potent as the (-)-isomer, the net ef- fect is p-stimulation Dobutamine is used as a cardiac stimulant after surgery or congestive heart failure As a catechol, dobutamine is readily metabolized by COMT and has a short duration of action with no oral activity

5.1.4 R 4 Substitution on the Aromatic Ring The natural 3',4'-dihydroxy substituted benzene ring present in norepinephrine pro- vides excellent receptor activity for both a-

and p-sites, but such catechol-containing com- pounds have poor oral bioavailability and short durations of action, even when adminis- tered intravenously, because they are rapidly metabolized by COMT Alternative substitu- tions have been found that retain good activity but are more resistant to COMT metabolism For example, 3'3'-dihydroxy compounds are not good substrates for COMT and, in addi- tion, provide selectivity for p,-receptors Thus, because of its ring-substitution pattern, metaproterenol (18) is an orally active bron- chodilator having little of the cardiac stimula- tory properties possessed by isoproterenol (17)

Other substitutions are possible that en- hance oral activity and provide selective p,-

activity, such as the 3'-hydroxymethyl, 4'-hy- droxy substitution pattern of albuterol (131, which is also not a substrate for COMT A re- cently developed selective p,-agonist with an extended duration of action is salmeterol(21), which has the same phenyl ring substitution

R4

as that of (13) but an unusually long and lipophilic group R1 on the nitrogen The octa- noltwater partition coefficient log P for salme- terol is 3.88 vs 0.66 for albuterol and the du- ration of action of salmeterol is 12 vs 4 h for albuterol (88) There is substantial evidence that the extended duration of action is attrib- uted to a specific binding interaction of the extended lipophilic side chain with a specific region of the P,-receptor, affording salmeterol

a unique binding mechanism (89) The long

Adrenergics and Adrenergic-Blocking Agents

lipophilic nitrogen substituent of salmeterol

has been shown, through a series of site-di-

rected mutagenesis experiments, to bind to a

specific 10 amino acid region of transmem-

brane domain 4 of the p,-adrenoceptor This

region, amino acids 149-158, is located at the

interface of the cyctoplasm and TMD4 Thus

"anchored" by the side chain, the remaining

part of the molecule can pivot and repetitively

stimulate the receptor through binding to as-

partate 113 of TMD3 and serines 204/207 of

TMD5 This lipophilic anchoring is postulated

to keep the drug localized at the site of action

and produce the long duration of action of

salmeterol

At least one of the phenyl substituents

must be capable of forming hydrogen bonds

and, if there is only one, it should be at the

4'-position to retain P-activity For example,

ritodrine (20) has only a 4'- OH for R4, yet

retains good p-activity with the large substitu-

ent on the nitrogen, making it P, selective

If R4 is only a 3'- OH, however, activity is

reduced at a-sites and almost eliminated at

p-sites, thus affording selective a-agonists

such as phenylephrine (11) and metaraminol

(8) Further indication that a-sites have a

wider range of substituent tolerance for ago-

nist activity is shown by the 2',5'-dimethoxy

substitution of methoxamine (91, which is a

selective a-agonist that also has p-blocking ac-

tivity at high concentrations

When the phenyl ring has no substituents

(i.e., R4 = H), phenylethylarnines may have

both direct and indirect activity Direct activ-

ity is the stimulation of a receptor by the drug

itself, whereas indirect activity is the result of

displacement of norepinephrine from its stor-

age granules, resulting in stimulation of the

receptor by the displaced norepinephrine Be-

cause norepinephrine stimulates both a- and

p-sites, indirect activity itself cannot be selec-

tive; however, stereochemistry of R1, R2,

andlor R4 may also play a role

For example, ephedrine erythro-(5) and

pseudoephedrine threo-(5) have the same sub-

stitution pattern and two asymmetric centers,

so there are four possible stereoisomers The

drug ephedrine is a mixture of the erythro en-

antiomers (1R,2S) and (IS,%); the threo pair

of enantiomers (1R,2R) and (1S,2S) consti- tute pseudoephedrine (?-ephedrine) Analo- gous to the catechol a-methylnorepinephrine (65, the active metabolite of methyldopa), the ephedrine stereoisomer with the (1R,2S) ab- solute configuration has direct activity on the receptors, both a and P, as well as an indirect component The ephedrine (IS,%) enantio- mer has primarily indirect activity Pseudo- ephedrine, the threo diastereomer of ephed- rine, has virtually no direct activity in either of its enantiomers and far fewer CNS side effects than those of ephedrine

on CNS stimulant and central appetite sup- pressant effects

Thus, tamsulosin has no utility in treating hypertension, but far fewer cardiovascular side effects than those of terazosin and dox- azosin in treating BPH

5.1.5 lmidazolines and Cuanidines Although

nearly all P-agonists are phenylethanolamine derivatives, a-adrenoceptors accommodate a far more diverse assortment of structures (80) Naphazoline (291, oxymetazoline (301,

5 Structure-Activity Relationships

tetrahydrozoline (311, and xylometazoline

(32) are selective a,-agonists and thus are va-

soconstrictors They all contain a one-carbon

bridge between C-2 of the imidazoline ring and

a phenyl substituent; thus, the general skeleton

of a phenylethylarnine is contained within the

structures Lipophilic substitution on the phe-

nyl ring ortho to the methylene bridge appears

to be required for agonist activity at both types

of a-receptor Bulky lipophilic groups attached

to the phenyl ring at the meta or para positions

provide selectivity for the a,-receptor by dimin-

ishing amnity for a,-receptors

Closely related to the imidazoline a,-ago-

nists are the aminoimidazolines, clonidine

(SS), apraclonidine (33), brimonidine (34); and

the structurally similar guanidines, guana-

benz (36) and guanfacine (37) Clonidine was

originally synthesized as a vasoconstricting

nasal decongestant but in early clinical trials

was found to have dramatic hypotensive ef-

fects, in contrast to all expectations for a vaso-

constrictor (90) Subsequent pharmacologic

investigations showed not only that clonidine

does have some a,-agonist (vasoconstrictive)

properties in the periphery but also that

clonidine is a powerful agonist at a,-receptors

in the CNS Stimulation of central postsyri8p-

tic a,-receptors leads to a reduction in sympa-

thetic neuronal output and a hypotensive

effect A very recent review thoroughly dis-

cusses the antihypertensive mechanism of ac-

tion of imidazoline a,-agonists and their rela-

tionship to a separate class of imidazoline

receptors (91)

Similar to the imidazoline a,-agonists,

clonidine has lipophilic ortho substituents on

the phenyl ring Chlorines afford better activ-

ity than methyls at a, sites The most readily

apparent difference between clonidine and the

a,-agonists is the replacement of the CH, on

C-1 of the imidazoline by an amine NH This

makes the imidazoline ring part of a guanidino

group, and the uncharged form of clonidine

exists as a pair of tautomers Clonidine has a

pK, value of 8.05 and at physiologic pH is

about 82% ionized The positive charge is

shared over all three nitrogens, and the two

rings are forced out of coplanarity by the bulk

of the two ortho chlorines as shown

The other imidazolines, (33) and (34), were synthesized as analogs of (35) and were dis- covered to have properties similar to those of a,-agonists After the discovery of clonidine, extensive research into the SAR of central a,-

agonists showed that the imidazoline ring was

not necessary for activity in this class For ex- ample, two ring-opened analogs of (35) result- ing from this effort are guanabenz (10) and guanfacine (37) These are ring-opened ana- logs of clonidine, and their mechanism of ac- tion is the same as that of clonidine

Tolazoline (41) has clear structural simi- larities to the imidazoline a-agonists, such as naphazoline and xylometazoline, but does not have the lipophilic substituents required for agonist activity Phentolamine (40) is also an imidazoline a-antagonist but the nature of its binding to a-adrenoceptors is not clearly un- derstood

5.1.6 Quinazolines Prazosin (43), the first known selective a,-blocker, was discovered in the late 1960s (92) and is now one of a small group of selective a,-antagonists, which in- cludes two other quinazoline antihyperten- sives, terazosin (44) (25, 93) and doxazosin (42) The latter, along with tamsulosin (241, was discovered to block a,-receptors in the prostate gland and alleviate the symptoms of benign prostatic hyperplasia (BPH)

The first three agents contain a Camino-

6,7-dimethoxyquinazoline ring system at-

tached to a piperazine nitrogen The only structural differences are in the groups at- tached to the other nitrogen of the piperazine, and the differences in these groups afford dra- matic differences in some of the pharmacoki- netic properties of these agents For example, when the furan ring of prazosin is reduced to form the tetrahydrofuran ring of terazosin, the compound becomes significantly more wa-

Adrenergics and Adrenergic-Blocking Agents

ter soluble (94), as would be expected, given

tetrahydrofuran's greater water solubility

than that of furan

5.1.7 Aryloxypropanolamines In general,

the aryloxypropanolamines are more potent

P-blockers than the corresponding aryletha-

nolamines, and most of the p-blockers currently

used clinically are aryloxypropanolamines

Beta-blockers have found wide use in treating

hypertension and certain types of glaucoma

At approximately this same time, a new se-

ries of Csubstituted phenyloxypropanolo-

lamines emerged, such as practolol, which

selectively inhibited sympathetic cardiac stim-

ulation These observations led to the recogni-

tion that not all preceptors were the same,

which led to the introduction of P, and P, no-

menclature to differentiate cardiac P-recep-

tors from others

Labetalol(26) and carvedilol(59) have un- usual activity, in that they are antihyperten- sives with a,-, PI-, and Pz-blocking activity In terms of SAR, you will recall from the earlier discussion of phenylethanolamine agonists that, although groups such as isopropyl and t-butyl eliminated a-receptor activity, still larger groups could bring back a,-affinity but not intrinsic activity Thus these two drugs have structural features permitting binding to both the a,- and both P-receptors The P-blocking activity of labetalol is approxi- mately 1.5 times that of its a-blocking activity The more recently developed carvedilol has an estimated P-blocking activity 10 to 100 times its a-blocking activity

A physicochemical parameter that has clin- ical correlation is relative lipophilicity of dif- ferent agents Propranolol is by far the most lipophilic of the available P-blockers and en-

6 Recent Developments

ters the CNS far better than less lipophilic

agents, such as atenolol or nadolol Lipophilic-

ity as measured by octanollwater partitioning

also correlates with primary site of clearance

The more lipophilic drugs are primarily

cleared by the liver, whereas the more hydro-

philic agents are cleared by the kidney This

could have an influence on choice of agents in

cases of renal failure or liver disease (27)

6 RECENT DEVELOPMENTS

Recently, major research efforts in develop-

ment of adrenergic drugs have focused largely

on efforts to discover new selective a,,-antag- onists for treatment of prostatic hypertrophy and to develop selective P,-agonists for use in treating obesity and type 2 diabetes

6.1 Selective a!,,-Adrenoceptor Antagonists

The successful application of tamsulosin (24)

to the treatment of BPH with minimal cardio- vascular effects has led to an extensive effort

to develop additional antagonists selective for the a,,-receptor Phenoxyethylamine (102, KMD-3213), a tamsulosin analog, has been re- ported to be in clinical trial in Japan, as has

(103) (95)

Other series of highly selective a,,-antag-

onists, and representative examples, are

arylpiperazines, arylpiperidines, and piperi-

dines, represented by (104), (1051, and (1061,

respectively Several compounds in these se-

ries have entered clinical trials, but little has

been reported about the outcomes (95) In ad-

dition to the review by Bock (951, two other

Adrenergics and Adrenergic-Blocking Agents

very thorough reviews of this field have re- cently been published (96,97)

6.2 Selective P,-Agonists

The other major area of recent emphasis in adrenergic drug research has been develop- ment of selective &-agonists to induce lipoly- sis in white adipose tissue This area has been extensively reviewed (4, 7, 8, 55, 98) Because obesity and diabetes are reaching epidemic proportions in the United States, an effective weight reduction has enormous therapeutic and market potential (99) As a consequence, there is a veritable avalanche of potential new drugs being published To date several com- pounds that looked promising in receptor as-

says and animal studies have entered clinical trials and failed The reader should consult the listed reviews for extensive descriptions of the progress in this field through 2000 Some

of the most promising recent candidates have been an extensive series of 3'-methvlsulfon- "

amido-4'-hydroxyphenylethanolamines pre- pared by competing groups Compounds (107) (BMS-194449) and (108) (BMS-196085) have both gone into clinical trial but are reported to have failed (100,101)

References

In a second series, compounds (109-111)

were reported as the most active derivatives in

the compounds reported in each study (102-

104) Finally, compounds (112) and (113)

from the same publication were reported to be

among the most potent and selective human

P3-agonists known to date (105)

Another group reported another series of

very selective P,-agonists in a series of cya-

noguanidine compounds The most potent and

selective in the series were reported to be

(114) and (115) (106)

The rate of publication in the two areas of

selective a,,-antagonists and selective P3-ago-

nists continues very high through the time

this chapter was written There is a large mar-

ket for a successful drug@ in either of these

areas and the level of competition in these ar-

eas will continue to be intense

10 R N Brogden, et al., Drugs, 21,81-89 (1981)

11 M C Beduschi, R Beduschi, and J E Oester- ling, Urology, 51,861-872 (1998)

12 B A Kenny, et al., Br J Pharmacol., 118, 871-878 (1996)

13 M I Wilde and D McTavish, Drugs, 52,883-

898 (1996)