J

50nm on

Dipole (permanent) [

Dipole [

Dipole

Complex

Hydrogen bond

A. Electrostatic attraction

A. Electrostatic attraction

Affinity And Avidity
C. Hydrophobic interaction

Ion on

Ionic bond on

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 biological 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 receptor. 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 activity), are unable to produce a full maximal response even when all receptors are occupied: lower efficacy. Ligand B is a partial agonist. The potency of an agonist can be expressed in terms of the concentration (EC50) at which the effect reaches one-half of its respective maximum.

Antagonists (A) attenuate the effect 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 rivals 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 presence of the antagonist, the concentration-response curve of the agonist is shifted to higher concentrations ("right-ward shift").

Molecular Models of Agonist/Antagonist Action (A)

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 reveal signs of spontaneous receptor activation. Selective binding of the agonist requires the receptor to be in the active conformation, thus promoting its existence. The "antagonist" displays affinity only for the inactive state and stabilizes the latter. When the system shows minimal spontaneous activity, application of an antagonist will not produce a measurable effect. When the system has high spontaneous activity, the antagonist may cause an effect that is the opposite of that of the agonist: inverse agonist.

A "true" antagonist lacking intrinsic activity ("neutral antagonist") displays equal affinity for both the active and inactive states of the receptor and does not alter basal activity of the cell. According to this model, a partial agonist shows lower selectivity for the active 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 decrease in affinity of the agonist. It is also possible that the allosteric deformation of the receptor increases affinity for an agonist, resulting in an allosteric synergism.

Functional antagonism. Two agonists affect the same parameter (e.g., bronchial diameter) via different receptors in the opposite direction (epineph-rine ^ dilation; histamine ^ constriction).

Agonist induces active conformation.

The agonist binds to the inactive receptor and thereby causes a change from the resting conformation to the active state. The antagonist binds to the inac-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

Atlas Pharmacology Lullmann
A. Molecular mechanisms of drug-receptor interaction
Drug Receptor Interaction
B. Potency and Efficacy of agonists

Agonist effect

Agonist effect

C. Competitive antagonism

Enantioselectivity of Drug Action

Many drugs are racemates, including p-blockers, nonsteroidal antiinflammatory 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., solubility, melting point) and both forms are usually obtained in equal amounts by chemical synthesis. As a result of enzymatic 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 rotation gives no clue concerning the spatial structure of enantiomers. The absolute configuration, as determined by certain rules, is described by the prefixes S and R. In some compounds, designation as the D- and L-form is possible by reference to the structure of D- and L-glyceraldehyde.

For drugs to exert biological actions, 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 affinity will then be higher. Thus, dexeti-mide displays an affinity at the musca-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

rinic ACh receptors almost 10000 times (p. 98) that of levetimide; and at p-adrenoceptors, S(-)-propranolol has an affinity 100 times that of the R(+)-form.

Enantioselectivity of intrinsic activity. The mode of attachment at the receptor also determines whether an effect is elicited and whether or not a substance has intrinsic activity, i.e., acts as an agonist or antagonist. For instance, (-) dobutamine is an agonist at a-adren-oceptors whereas the (+)-enantiomer is an antagonist.

Inverse enantioselectivity at another receptor. An enantiomer may possess an unfavorable configuration at one receptor that may, however, be optimal for interaction with another receptor. In the case of dobutamine, the (+)-enantiomer has affinity at p-adreno-ceptors 10 times higher than that of the (-)-enantiomer, both having agonist activity. However, the a-adrenoceptor stimulant action is due to the (-)-form (see above).

As described for receptor interactions, 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.

A. Example of an enantiomeric pair with different affinity for a stereoselective receptor

B. Reasons for different pharmacological properties of enantiomers

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 a-helical membrane-spanning domains probably form a circle around a central pocket that carries the attachment sites for the mediator substance. Binding of the mediator molecule or of a structurally related agonist molecule induces a change in the conformation of the receptor protein, 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 a, p, and y There are various G-proteins that differ mainly with regard to their a-unit Association with the receptor activates the G-protein, leading in turn to activation of another protein (enzyme, ion channel). A large number of mediator substances act via G-protein-coupled receptors (see p. 66 for more details).

An example of a ligand-gated ion channel (B) is the nicotinic cholinocep-tor of the motor endplate. The receptor complex consists of five subunits, each of which contains four transmembrane domains. Simultaneous binding of two acetylcholine (ACh) molecules to the two a-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 a and p sub-units (a2p2). Some of the receptors for the transmitter y-aminobutyric acid (GABA) belong to this receptor family:

the GABAA subtype is linked to a chloride channel (and also to a benzodiaze-pine-binding site, see p. 227). Glutamate and glycine both act via ligand-gated ion channels.

The insulin receptor protein represents 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 hormones also belong to the catalytic receptor class.

Protein synthesis-regulating receptors (D) for steroids, thyroid hormone, and retinoic acid are found in the cytosol and in the cell nucleus, respectively.

Binding of hormone exposes a normally hidden domain of the receptor protein, thereby permitting the latter to bind to a particular nucleotide sequence on a gene and to regulate its transcription. Transcription is usually initiated or enhanced, rarely blocked.

Amino acids

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