Tài liệu Color Atlas of Pharmacology (Part 7): Drug-Receptor Interaction doc

Agonists – AntagonistsAn agonist has affinity binding avidity for its receptor and alters the receptor protein in such a manner as to generate a stimulus that elicits a change in cell fu

Types of Binding Forces

Unless a drug comes into contact with

intrinsic structures of the body, it

can-not affect body function

Covalent bond Two atoms enter a

covalent bond if each donates an

elec-tron to a shared elecelec-tron pair (cloud)

This state is depicted in structural

for-mulas by a dash The covalent bond is

“firm”, that is, not reversible or only

poorly so Few drugs are covalently

bound to biological structures The

bond, and possibly the effect, persist for

a long time after intake of a drug has

been discontinued, making therapy

dif-ficult to control Examples include

alky-lating cytostatics (p 298) or

organo-phosphates (p 102) Conjugation

reac-tions occurring in biotransformation

al-so represent a covalent linkage (e.g., to

glucuronic acid, p 38)

Noncovalent bond There is no

for-mation of a shared electron pair The

bond is reversible and typical of most

drug-receptor interactions Since a drug

usually attaches to its site of action by

multiple contacts, several of the types of

bonds described below may participate

Electrostatic attraction (A) A

pos-itive and negative charge attract each

other

Ionic interaction:An ion is a particle

charged either positively (cation) or

negatively (anion), i.e., the atom lacks or

has surplus electrons, respectively

At-traction between ions of opposite

charge is inversely proportional to the

square of the distance between them; it

is the initial force drawing a charged

drug to its binding site Ionic bonds have

a relatively high stability

Dipole-ion interaction:When bond

electrons are asymmetrically

distribut-ed over both atomic nuclei, one atom

will bear a negative (!–), and its partner

a positive (!+) partial charge The

mole-cule thus presents a positive and a

nega-tive pole, i.e., has polarity or a dipole A

partial charge can interact

electrostati-cally with an ion of opposite charge

Dipole-dipole interactionis the

elec-trostatic attraction between opposite

partial charges When a hydrogen atom bearing a partial positive charge bridges two atoms bearing a partial negative charge, a hydrogen bond is created

A van der Waals’ bond (B) is

formed between apolar molecular groups that have come into close prox-imity Spontaneous transient distortion

of electron clouds (momentary faint di-pole, !!) may induce an opposite dipole

in the neighboring molecule The van der Waals’ bond, therefore, is a form of electrostatic attraction, albeit of very low strength (inversely proportional to the seventh power of the distance)

Hydrophobic interaction (C) The

attraction between the dipoles of water

is strong enough to hinder intercalation

of any apolar (uncharged) molecules By tending towards each other, H2O mole-cules squeeze apolar particles from their midst Accordingly, in the organ-ism, apolar particles have an increased probability of staying in nonaqueous, apolar surroundings, such as fatty acid chains of cell membranes or apolar re-gions of a receptor

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C Hydrophobic interaction

A Electrostatic attraction

B van der Waals’ bond

Drug + Binding site Complex

Ionic bond Ion

Dipole Ion

Hydrogen bond Dipole

Dipole (permanent)

Ion

50nm

1.5nm

0.5nm

Induced transient fluctuating dipoles

polar

Apolar

acyl chain

"Repulsion" of apolar

Insertion in apolar membrane interior

apolar

Adsorption to apolar surface

!+

!"

–

!+

!!+

!!–

!!–

!!+

!!–

!!+

!!+

!!–

= Drug

!–

!+

+

!–

!+

!–

!+

!–

!+

!+

–

–

D

D

D

D

D

Agonists – Antagonists

An agonist has affinity (binding avidity)

for its receptor and alters the receptor

protein in such a manner as to generate

a stimulus that elicits a change in cell

function: “intrinsic activity“ The

bio-logical effect of the agonist, i.e., the

change in cell function, depends on the

efficiency of signal transduction steps

(p 64, 66) initiated by the activated

re-ceptor Some agonists attain a maximal

effect even when they occupy only a

small fraction of receptors (B, agonist

A) Other ligands (agonist B), possessing

equal affinity for the receptor but lower

activating capacity (lower intrinsic

ac-tivity), are unable to produce a full

max-imal response even when all receptors

are occupied: lower efficacy Ligand B is

a partial agonist The potency of an

ago-nist can be expressed in terms of the

concentration (EC50) at which the effect

reaches one-half of its respective

maxi-mum

Antagonists (A) attenuate the

ef-fect of agonists, that is, their action is

“anti-agonistic”

Competitive antagonists possess

affinity for receptors, but binding to the

receptor does not lead to a change in

cell function (zero intrinsic activity).

When an agonist and a competitive

antagonist are present simultaneously,

affinity and concentration of the two

ri-vals will determine the relative amount

of each that is bound Thus, although the

antagonist is present, increasing the

concentration of the agonist can restore

the full effect (C) However, in the

pres-ence of the antagonist, the

concentra-tion-response curve of the agonist is

shifted to higher concentrations

(“right-ward shift”)

Molecular Models of Agonist/Antagonist

Action (A)

Agonist induces active conformation.

The agonist binds to the inactive

recep-tor and thereby causes a change from

the resting conformation to the active

state The antagonist binds to the

inac-tive receptor without causing a confor-mational change

Agonist stabilizes spontaneously occurring active conformation The

receptor can spontaneously “flip” into the active conformation However, the statistical probability of this event is usually so small that the cells do not re-veal signs of spontaneous receptor

acti-vation Selective binding of the agonist

requires the receptor to be in the active conformation, thus promoting its

exis-tence The “antagonist” displays affinity

only for the inactive state and stabilizes the latter When the system shows min-imal spontaneous activity, application

of an antagonist will not produce a mea-surable effect When the system has high spontaneous activity, the antago-nist may cause an effect that is the

op-posite of that of the agonist: inverse

ago-nist

A “true” antagonist lacking intrinsic activity (“neutral antagonist”) displays equal affinity for both the active and in-active states of the receptor and does not alter basal activity of the cell

According to this model, a partial

ago-nist shows lower selectivity for the ac-tive state and, to some extent, also binds

to the receptor in its inactive state

Other Forms of Antagonism Allosteric antagonism The antagonist

is bound outside the receptor agonist

binding site proper and induces a de-creasein affinity of the agonist It is also possible that the allosteric deformation

of the receptor increases affinity for an

agonist, resulting in an allosteric syner-gism.

Functional antagonism Two

ago-nists affect the same parameter (e.g., bronchial diameter) via different recep-tors in the opposite direction (epineph-rine ! dilation; histamine ! constric-tion)

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induces active

conformation of

receptor protein

C Competitive antagonism

A Molecular mechanisms of drug-receptor interaction

B Potency and Efficacy of agonists

Antagonist Agonist

Receptor

Antagonist occupies receptor without con-formational change

Agonist selects active receptor conformation

Rare spontaneous transition

Antagonist selects inactive receptor conformation inactive

Potency Concentration (log) of agonist

Receptor occupation Increase in tension

Agonist concentration (log)

Agonist effect

Concentration of

antagonist

Agonist A

Agonist B smooth

muscle cell

Receptors

active

10000

Enantioselectivity of Drug Action

Many drugs are racemates, including

!-blockers, nonsteroidal

anti-inflammato-ry agents, and anticholinergics (e.g.,

benzetimide A) A racemate consists of

a molecule and its corresponding mirror

image which, like the left and right

hand, cannot be superimposed Such

chiral (“handed”) pairs of molecules are

referred to as enantiomers Usually,

chirality is due to a carbon atom (C)

linked to four different substituents

(“asymmetric center”) Enantiomerism is

a special case of stereoisomerism

Non-chiral stereoisomers are called

diaster-eomers (e.g., quinidine/quinine).

Bond lengths in enantiomers, but

not in diastereomers, are the same

Therefore, enantiomers possess similar

physicochemical properties (e.g.,

solu-bility, melting point) and both forms are

usually obtained in equal amounts by

chemical synthesis As a result of

enzy-matic activity, however, only one of the

enantiomers is usually found in nature

In solution, enantiomers rotate the

wave plane of linearly polarized light

in opposite directions; hence they are

refered to as “dextro”- or “levo-rotatory”,

designated by the prefixes d or (+) and l

or (-), respectively The direction of

ro-tation gives no clue concerning the

spa-tial structure of enantiomers The

abso-lute configuration, as determined by

certain rules, is described by the

prefix-es S and R In some compounds, dprefix-esig-

desig-nation as the D- and L-form is possible

by reference to the structure of D- and

L-glyceraldehyde

For drugs to exert biological

ac-tions, contact with reaction partners in

the body is required When the reaction

favors one of the enantiomers,

enantio-selectivity is observed

Enantioselectivity of affinity If a

receptor has sites for three of the

sub-stituents (symbolized in B by a cone, a

sphere, and a cube) on the asymmetric

carbon to attach to, only one of the

enantiomers will have optimal fit Its

af-finity will then be higher Thus,

dexeti-midedisplays an affinity at the

musca-rinic ACh receptors almost 10000 times

(p 98) that of levetimide; and at

!-adrenoceptors, S(-)-propranolol has an affinity 100 times that of the R(+)-form

Enantioselectivity of intrinsic ac-tivity The mode of attachment at the

receptor also determines whether an ef-fect is elicited and whether or not a sub-stance has intrinsic activity, i.e., acts as

an agonist or antagonist For instance,

(-) dobutamine is an agonist at

"-adren-oceptors whereas the (+)-enantiomer is

an antagonist

Inverse enantioselectivity at an-other receptor An enantiomer may

possess an unfavorable configuration at one receptor that may, however, be op-timal for interaction with another

re-ceptor In the case of dobutamine, the

(+)-enantiomer has affinity at !-adreno-ceptors 10 times higher than that of the (-)-enantiomer, both having agonist ac-tivity However, the "-adrenoceptor stimulant action is due to the (-)-form (see above)

As described for receptor interac-tions, enantioselectivity may also be manifested in drug interactions with

enzymes and transport proteins

Enan-tiomers may display different affinities and reaction velocities

Conclusion: The enantiomers of a

racemate can differ sufficiently in their pharmacodynamic and

pharmacokinet-ic properties to constitute two distinct drugs

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

Transport pr

B Reasons for different pharmacological properties of enantiomers

A Example of an enantiomeric pair with different affinity for

A a stereoselective receptor

Physicochemical properties equal Deflection of polarized light

D Absolute configuration

Potency (rel affinity at m-ACh-receptors

+ 125°

(Levorotatory

RACEMATE Benzetimide ENANTIOMER

Intrinsic

Pharmacodynamic

Affinity

Transport protein

Receptor Types

Receptors are macromolecules that bind

mediator substances and transduce this

binding into an effect, i.e., a change in

cell function Receptors differ in terms

of their structure and the manner in

which they translate occupancy by a

li-gand into a cellular response (signal

transduction).

G-protein-coupled receptors (A)

consist of an amino acid chain that

weaves in and out of the membrane in

serpentine fashion The

extramembra-nal loop regions of the molecule may

possess sugar residues at different

N-glycosylation sites The seven !-helical

membrane-spanning domains probably

form a circle around a central pocket

that carries the attachment sites for the

mediator substance Binding of the

me-diator molecule or of a structurally

re-lated agonist molecule induces a change

in the conformation of the receptor

pro-tein, enabling the latter to interact with

a G-protein (= guanyl

nucleotide-bind-ing protein) G-proteins lie at the inner

leaf of the plasmalemma and consist of

three subunits designated !, ", and #

There are various G-proteins that differ

mainly with regard to their !-unit

As-sociation with the receptor activates the

G-protein, leading in turn to activation

of another protein (enzyme, ion

chan-nel) A large number of mediator

sub-stances act via G-protein-coupled

re-ceptors (see p 66 for more details)

An example of a ligand-gated ion

channel (B) is the nicotinic

cholinocep-tor of the mocholinocep-tor endplate The recepcholinocep-tor

complex consists of five subunits, each

of which contains four transmembrane

domains Simultaneous binding of two

acetylcholine (ACh) molecules to the

two !-subunits results in opening of the

ion channel, with entry of Na+(and exit

of some K+), membrane depolarization,

and triggering of an action potential (p

82) The ganglionic N-cholinoceptors

apparently consist only of ! and "

sub-units (!2"2) Some of the receptors for

the transmitter #-aminobutyric acid

(GABA) belong to this receptor family:

the GABAAsubtype is linked to a chlo-ride channel (and also to a benzodiaze-pine-binding site, see p 227) Gluta-mate and glycine both act via ligand-gated ion channels

The insulin receptor protein

repre-sents a ligand-operated enzyme (C), a

catalytic receptor When insulin binds

to the extracellular attachment site, a tyrosine kinase activity is “switched on”

at the intracellular portion Protein phosphorylation leads to altered cell function via the assembly of other signal proteins Receptors for growth hor-mones also belong to the catalytic re-ceptor class

Protein synthesis-regulating re-ceptors (D) for steroids, thyroid

hor-mone, and retinoic acid are found in the cytosol and in the cell nucleus, respec-tively

Binding of hormone exposes a nor-mally hidden domain of the receptor protein, thereby permitting the latter to bind to a particular nucleotide sequence

on a gene and to regulate its transcrip-tion Transcription is usually initiated or enhanced, rarely blocked

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Amino acids

D Protein synthesis-regulating receptor

A G-Protein-coupled receptor

B Ligand-gated ion channel C Ligand-regulated enzyme

Nicotinic acetylcholine receptor

Subunit consisting of four trans-membrane domains

Na+

K+

Na +

K +

"

$

#

Insulin

S S

Tyrosine kinase

Phosphorylation of tyrosine-residues in proteins

COOH

Effect

G-Protein Agonist

COOH

!-Helices

Transmembrane domains

Steroid

Nucleus Cytosol

Receptor

Tran-scription

Trans-lation

7 5 4

Mode of Operation of

G-Protein-Coupled Receptors

Signal transduction at

G-protein-cou-pled receptors uses essentially the same

basic mechanisms (A) Agonist binding

to the receptor leads to a change in

re-ceptor protein conformation This

change propagates to the G-protein: the

!-subunit exchanges GDP for GTP, then

dissociates from the two other subunits,

associates with an effector protein, and

alters its functional state The !-subunit

slowly hydrolyzes bound GTP to GDP

G!-GDP has no affinity for the effector

protein and reassociates with the " and

# subunits (A) G-proteins can undergo

lateral diffusion in the membrane; they

are not assigned to individual receptor

proteins However, a relation exists

between receptor types and G-protein

types (B) Furthermore, the !-subunits

of individual G-proteins are distinct in

terms of their affinity for different

effec-tor proteins, as well as the kind of

influ-ence exerted on the effector protein G!

-GTP of the GS-protein stimulates

adeny-late cyclase, whereas G!-GTP of the Gi

-protein is inhibitory The G protein-

G-protein-coupled receptor family includes

mus-carinic cholinoceptors, adrenoceptors

for norepinephrine and epinephrine,

re-ceptors for dopamine, histamine,

serot-onin, glutamate, GABA, morphine,

pros-taglandins, leukotrienes, and many

oth-er mediators and hormones

Major effector proteins for

G-pro-tein-coupled receptors include

adeny-late cyclase (ATP ! intracellular

mes-senger cAMP), phospholipase C

(phos-phatidylinositol ! intracellular

mes-sengers inositol trisphosphate and

di-acylglycerol), as well as ion channel

proteins Numerous cell functions are

regulated by cellular cAMP

concentra-tion, because cAMP enhances activity of

protein kinase A, which catalyzes the

transfer of phosphate groups onto

func-tional proteins Elevation of cAMP levels

inter alialeads to relaxation of smooth

muscle tonus and enhanced

contractil-ity of cardiac muscle, as well as

in-creased glycogenolysis and lipolysis (p

84) Phosphorylation of cardiac cal-cium-channel proteins increases the probability of channel opening during membrane depolarization It should be noted that cAMP is inactivated by phos-phodiesterase Inhibitors of this enzyme elevate intracellular cAMP concentra-tion and elicit effects resembling those

of epinephrine

The receptor protein itself may undergo phosphorylation, with a resul-tant loss of its ability to activate the as-sociated G-protein This is one of the mechanisms that contributes to a de-crease in sensitivity of a cell during pro-longed receptor stimulation by an

ago-nist (desensitization).

Activation of phospholipase C leads

to cleavage of the membrane phospho-lipid phosphatidylinositol-4,5

bisphos-phate into inositol trisphosbisphos-phate (IP3)

and diacylglycerol (DAG) IP3promotes release of Ca2+from storage organelles, whereby contraction of smooth muscle cells, breakdown of glycogen, or exocy-tosis may be initiated Diacylglycerol stimulates protein kinase C, which phosphorylates certain serine- or threo-nine-containing enzymes

The !-subunit of some G-proteins

may induce opening of a channel pro-tein In this manner, K+channels can be activated (e.g., ACh effect on sinus node,

p 100; opioid action on neural impulse transmission, p 210)

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

B G-Proteins, cellular messenger substances, and effects

A G-Protein-mediated effect of an agonist

Receptor G-Protein Effector

GDP

GTP

ATP

cAMP

Protein kinase A

Phosphorylation of

functional proteins

Activation Phosphorylation

of enzymes

IP3

Ca2+

P

DAG

Facilitation

of ion channel opening

Transmembrane ion movements Effect on:

e g., Glycogenolysis

lipolysis

Ca-channel

activation

e g., Contraction

of smooth muscle, glandular secretion

e g., Membrane action potential, homeostasis of cellular ions

"

#

!

! " #