Friday, 12 July 2019

Drug-Receptor Interaction

Drug-Receptor Interaction

Drug-Receptor Interaction

Agonists – Antagonists

An agonist has an 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 an 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 (EC 50 ) 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 an 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 (“rightward shift”).

Molecular Models of Agonist/Antagonist
Action (A)

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 inactive receptor without causing a conformational change. on 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 an equal affinity for both the active and inactive states of the receptor and does not alter the 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 the 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 (epinephrine ? dilation; histamine ? constriction).

Drug-Receptor Interaction

Drug-Receptor Interaction
Drug-Receptor Interaction

Enantioselectivity of Drug Action

Many drugs are racemates, including β-blockers, nonsteroidal anti-inflammatory 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. Nonchiral stereoisomers are called diastereomers (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 “levorotatory”, 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

For drugs to exert biological actions, contact with reaction partners in the body is required. When the reaction favors one of the enantiomers, enantioselectivity is observed.

Enantioselectivity of affinity. If a receptor has sites for three of the substituents (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 the optimal fit. Its affinity will then be higher. Thus, dexetimide displays an affinity at the muscarinic ACh receptors almost 10000 times (p. 98) that of levetimide; and at β 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 α-adrenoceptors 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 β-adrenoceptors 10 times higher than that of the (-)-enantiomer, both having agonist activity. However, the α-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. Enantiomers may display different affinities and reaction velocities. Conclusion: The enantiomers of a racemate can differ sufficiently in their pharmacodynamic and pharmacokinetic properties to constitute two distinct drugs.

Drug-Receptor Interaction
Drug-Receptor Interaction

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 ligand 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 a serpentine fashion. The extra membranal loop regions of the molecule may possess sugar residues at different N- glycosylation sites. The seven α-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-binding protein). G-proteins lie at the inner leaf of the plasmalemma and consist of three subunits designated α, β, and γ. There are various G-proteins that differ mainly with regard to their α-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 choline receptor 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 α-subunits results in the opening of the ion channel, with the entry of Na + (and exit of some K + ), membrane depolarization, and triggering of an action potential (p. 82). The ganglionic N-choline captors apparently consist only of α and β subunits (α 2 β 2 ). Some of the receptors for the transmitter γ-aminobutyric acid (GABA) belong to this receptor family: the GABA A subtype is linked to a chloride channel (and also to a benzodiazepine-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. 

Drug-Receptor Interaction
Drug-Receptor Interaction
Drug-Receptor Interaction

Mode of Operation of G-Protein-Coupled Receptors

Signal transduction at G-protein-coupled receptors uses essentially the same basic mechanisms (A). Agonist binding to the receptor leads to a change in receptor protein conformation.  This change propagates to the G-protein: the α-subunit exchanges GDP for GTP then dissociates from the two other subunits, associates with an effector protein, and alters its functional state. The α-subunit slowly hydrolyzes bound GTP to GDP. G α -GDP has no affinity for the effector protein and reassociates with the β and γ 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 α-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. G α - GTP of the GS -protein stimulates adenylate cyclase, whereas G α -GTP of the Gi protein is inhibitory. The G-protein-coupled receptor family includes muscarinic choline receptors, adrenoceptors
for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones.

Major effector proteins for G-protein-coupled receptors include adenylate cyclase (ATP ? intracellular messenger cAMP), phospholipase C (phosphatidylinositol ? intracellular messengers inositol trisphosphate and diacylglycerol), as well as ion channel proteins. Numerous cell functions are regulated by cellular cAMP concentration because cAMP enhances the activity of protein kinase A, which catalyzes the transfer of phosphate groups onto functional proteins. Elevation of cAMP levels
inter alia leads to relaxation of smooth muscle tonus and enhanced contractility of cardiac muscle, as well as increased glycogenolysis and lipolysis (p.84). Phosphorylation of cardiac calcium-channel proteins increases the probability of channel opening during membrane depolarization. It should be noted that cAMP is inactivated by phosphodiesterase. Inhibitors of this enzyme elevate intracellular cAMP concentration and elicit effects resembling those of epinephrine.

The receptor protein itself may undergo phosphorylation, with a resultant loss of its ability to activate the associated G-protein. This is one of the mechanisms that contribute to a decrease in sensitivity of a cell during prolonged receptor stimulation by an agonist (desensitization).

Activation of phospholipase C leads to cleavage of the membrane phospholipid phosphatidylinositol-4,5 bisphosphate into inositol trisphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 promotes the release of Ca 2+ from storage organelles, whereby contraction of smooth muscle cells, breakdown of glycogen, or exocytosis may be initiated. Diacylglycerol stimulates protein kinase C, which phosphorylates certain serine- or threonine-containing enzymes.

The α-subunit of some G-proteins may induce opening of a channel protein. 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).
Drug-Receptor Interaction

Drug-Receptor Interaction

Time Course of Plasma Concentration
and Effect

After the administration of a drug, its concentration in plasma rises, reaches a peak, and then declines gradually to the starting level, due to the processes of distribution and elimination (p. 46). Plasma concentration at a given point in time depends on the dose administered. Many drugs exhibit a linear relationship between plasma concentration and dose within the therapeutic range (dose-linear kinetics; (A); note different scales on the ordinate). However, the same does not apply to drugs whose elimination processes are already sufficiently activated at therapeutic plasma levels so as to preclude further propor- tional increases in the rate of elimination when the concentration is increased further. Under these conditions, a smaller proportion of the dose administered is eliminated per unit of time.

The time course of the effect and of the concentration in plasma are not identical, because the concentration- effect relationships obey a hyperbolic function (B; cf. also p. 54). This means that the time course of the effect exhibits dose dependence also in the presence of dose-linear kinetics (C).
In the lower dose range (example 1), the plasma level passes through a concentration range (0 ? 0.9) in which the concentration effect relationship is quasi-linear. The respective time courses of plasma concentration and effect (A and C, left graphs) are very similar.

However, if a high dose (100) is applied, there is an extended period of time during which the plasma level will remain in a concentration range (between 90 and 20) in which a change in concentration does not cause a change in the size of the effect. Thus, at high doses (100), the time-effect curve exhibits a kind of plateau. The effect declines only when the plasma level has returned (below 20) into the range where a change in plasma level causes a change in the intensity of the effect.

The dose dependence of the time course of the drug effect is exploited when the duration of the effect is to be prolonged by the administration of a dose in excess of that required for the effect. This is done in the case of penicillin G (p. 268) when a dosing interval of 8h is being recommended, although the drug is eliminated with a half-life of 30 min. This procedure is, of course, feasible only if supramaximal dosing is not associated with toxic effects. Furthermore, it follows that a nearly constant effect can be achieved, although the plasma level may fluctuate greatly during the interval between doses.

The hyperbolic relationship between plasma concentration and effect explains why the time course of the effect, unlike that of the plasma concentration, cannot be described in terms of a simple exponential function. A half-life can be given for the processes of drug absorption and elimination, hence for the change in plasma levels, but generally not for the onset or decline of the effect.

Drug-Receptor Interaction
Drug-Receptor Interaction
Drug-Receptor Interaction

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