Drug receptor theories by siva

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Drug Receptor Theory:

Prepared & Presented by Dr. Siva Reddy Challa, Professor & HOD, Dept. of Pharmacology KVSR Siddhartha College of Pharmaceutical Sciences, Siddhartha Nagar, Vijayawada-520010 Andhra Pradesh, INDIA Email: sivareddypharma@gmail.com Drug Receptor Theory

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First postulated by John Langley (1878) Established after his experiments using nicotine and curare analogues on muscle contraction. Isolated muscle fibers: pilocarpine (contraction) and atropine (inhibition). Two compounds competing for a third, but unknown substrate. Furthered by Paul Ehrlich (1854-1915) Demonstrated that stereoselectivity was imperative in drug-receptor signaling.

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John Langley In 1901, Langley challenged the dominant hypothesis that drugs act at nerve endings by demonstrating that nicotine acted at sympathetic ganglia even after the degeneration of the severed preganglionic nerve endings. That year, Langley also discovered for himself a tool in the form of renal extract (containing adrenaline) which produced sympathomimetic responses when applied to tissues exogenously. But it was not until 1905 that Langley published the results of the decisive experiments using systemic injections of curare and nicotine given to chicks. It was through these experiments that Langley concluded the existence of a receptive substance in striated muscle.

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Muscle Fiber Drugs only act here?? What about drugs acting here, also??

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Postulates of receptor theory Receptors must possess structural and steric specificity. Receptors are saturable and finite (limited number of binding sites) Receptors must possess high affinity for its endogenous ligand at physiological concentrations Once the endogenous ligand binds to the receptor, some early recognizable chemical event must occur

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Receptor must possess structural and steric specificity for a hormone and for its close analogs as well. Receptors are saturable and limited (i.e. there is a finite number of binding sites). Hormone-receptor binding is cell specific in accordance with target organ specificity. Receptor must possess a high affinity for the hormone at physiological concentrations . Once a hormone binds to the receptor, some recognizable early chemical event must occur.

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Recognition: The receptor protein must exist in a conformational state that allows for recognition and binding of a compound and must satisfy the following criteria: Saturability – receptors exists in finite numbers. Reversibility – binding must occur non-covalently due to weak intermolecular forces (H-bonding, vander Waal forces). Stereoselectivity – receptors should recognize only one of the naturally occurring optical isomers (+ or -, d or l, or S or R). Agonist specificity – structurally related drugs should bind well, while physically dissimilar compounds should bind poorly. Tissue specificity – binding should occur in tissues known to be sensitive to the endogenous ligand. Binding should occur at physiologically relevant concentrations.

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Assumptions of the law of mass action. All receptors are equally accessible to ligand. No partial binding occurs; receptors are either free of ligand or bound with ligand. Ligand is nor altered by binding Binding is reversible Different affinity states?????

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Clarke’s Receptor occupation theory The occupancy model was the first model put forward by Clark to explain the activity of drugs at receptors quantified the relationship between drug concentration and observed effect. It is based on mass-action kinetics and attempts to link the action of a drug to the proportion of receptors occupied by that drug at equilibrium. In particular that the magnitude of the response is directly proportional to the amount of drug bound and that the maximum response would be elicited once all receptors were occupied at equilibrium.

Limitations of Clarkes receptor occupation theory:

Limitations of Clarkes receptor occupation theory Not all compounds that bind to a receptor elicit a response (Eg: antagonist). This theory does not explain about partial agonism. This theory does not explain about spare receptors. The flaw in Clarks receptor-occupancy model was that it was insufficient to explain the concept of partial agonist lead to the development of agonist models of drug action by Ariens in 1954 and by Stephenson in 1956 to account for the intrinsic activity (efficacy) of a drug (that is, its ability to induce an effect after binding). This theory does not explain about constitutional receptor activity, inverse agonism, Cooperativity, allosteric modulation.

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Activation of membrane receptors and target cell responses is proportional to the degree of receptor occupancy.

Following Clarkes and Ariens drug receptor theories: Definitions are as follows :

Following Clarkes and Ariens drug receptor theories: Definitions are as follows

Paton’s Rate theory:

Paton’s Rate theory This model describes the effect is produced by the drug molecules based on the rates of association and dissociation of drugs to and from the receptors. Antagonists act much more slowly than agonists do and hence the rate of dissociation is inversely proportional to the potencies of antagonists while is direcly proportional to the antagonists. This explians phenomenon “ fade” which is observed when an agonist produces a very transient peak (E peak ) effect followed by steady state response (equilibrium effect i.e equal to E max). Type of effect is independent of number of receptors rather rate of binding and release from the receptor.

Two state Receptor theory:

Two state Receptor theory

Ternary complex model:

Ternary complex model The original Ternary complex model was used to describe ligand, receptor, and G-protein interactions uses equilibrium dissociation constants for the interactions between the receptor and each ligand (K a for ligand A; K b for ligand B). This model mainly discussed about allosteric modulators. This model described a cooperativity factor (α) that denotes the mutual effect of the two ligands on each other’s affinity for the receptor. An α < 1.0 refers to positive cooperativity , an α > 1.0 refers to negative cooperativity , and an α = 1.0 means that binding of either ligand to the receptor does not alter the affinity of the other ligand for the receptor (i.e., a neutral modulator).

Classical theory of antagonism:

Classical theory of antagonism The development of the classic theory of drug antagonism by Gaddum, Schild and Arunlakshana built on the work of Langley, Hill and Clark. Gaddum described a model for the competitive binding of two ligands to the same receptor in short communication to the Physiological Society in 1937. The description referred only to binding, it was not immediately useful for the analysis of experimental measurements of the effects of antagonists on the response to agonists. Schild who made measurement of the equilibrium constant for the binding of an antagonist possible. he developed the Schild equation to determine a dose ratio a measure of the potency of a drug.

Classical theory of antagonism:

Classical theory of antagonism In Schild regression the change in the dose ratio, the ratio of the EC 50 of an agonist alone compared to the EC 50 in the presence of a competitive antagonist as determined on a dose response curve used to determine the affinity of an antagonist for its receptor.

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Competitive Antagonism

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