Occupancy theory, receptors

The conservation equation for receptors defines the total number of receptors as the sum of bound and free receptors (Equation (6.3)). Although the receptor population is in fact made up of subpopulations of receptors in high- and low-affinity states, this is most relevant for modeling agonist interactions. Because most tracers are radiolabeled antagonists, this simplified model is sufficient for most tracer studies. The conservation and mass action equations (Equations (6.3) and (6.4)) can be rearranged to calculate the number of bound receptors  

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DIFFUSION OF LIGAND TO RECEPTOR DRUG RECEPTOR OCCUPANCY THEORY OF DRUG ACTION... 

The receptor occupation theory of drug action equates drug effect to receptor occupancy. The intensity of drug effect is proportional to the number of receptors that are occupied by drug and the maximum effect occurs when all receptors are occupied by drug. 

Pharmacodynamics describes the time course and the magnitude of pharmacological response of drugs. Based on the classic receptor-occupancy theory, after drug molecules reach the target biophase, it binds to the receptors to form the drug-receptor complex to exert pharmacological response (Fig. 2). 

Emax Model, ftmax model was originally derived from the classic drug-receptor occupancy theory. It is an empirical function for describing a non-linear concentration-effect relationship with the general form ... 

PD, on the other hand, describes the effect of the drug on the body and is based on the fundamental principles founded on the receptor occupancy theory (see Fig. 1) [1]. PD is driven by the nature of the drug-receptor interaction, which is affected by the number and affinity of receptors, as well as the drug concentration at the receptor site. This underlies the importance of achieving a sustained steady-state effective concentration of drugs in the ffuids bathing... 

Receptor occupancy theory, in which it is assumed that response emanates from a receptor occupied by a drug, has its basis in the law of mass action. The basic currency of receptor pharmacology is the dose-response curve, a depiction of the observed effect of a drug as a function of its... 

The various components of classical theory relating receptor occupancy to tissue response are shown schematically in Figure 3.5. It will be seen that this formally is identical to the equation for response derived in the operational model (see material following), where x = [Rt]e/p. 

FIGURE 3.5 Major components of classical receptor theory. Stimulus is the product of intrinsic efficacy (s), receptor number [R], and fractional occupancy as given by the Langmuir adsorption isotherm. A stimulus-response transduction function f translates this stimulus into tissue response. The curves defining receptor occupancy and response are translocated from each other by the stimulus-response function and intrinsic efficacy. 

The law of mass action has been successfully applied to many drug dose-response relationships since the early work of Clark. The systematic relation between the dose of a drug and the magnitude of its response is based on three assumptions (1) response is proportional to the level of receptor occupancy (occupancy theory), (2) one drug molecule combines with one receptor site, and (3) a negligible fraction of total drug is combined with the receptors. These assumptions must also apply to Beidler s equation. 

The biological or functional response to receptor activation can be assumed to be directly proportional to the number of receptors (R) occupied by a given ligand (L) at equilibrium. This assumption is termed the occupancy theory of drug response. The equation describing this phenomenon was proposed as ... 

The classical occupation theory of Clark rests on the assumption that drugs interact with independent binding sites and activate them, resulting in a biological response that is proportional to the amount of drug-receptor complex formed. The response ceases when this complex dissociates. Assuming a bimolecular reaction, one can write... 

In contrast to the assumption made in the classical occupation theory, the agonist in the two-state model does not activate the receptor but shifts the equilibrium toward the R form. This explains why the number of occupied receptors does not equal the number of activated receptors. 

Occupancy theory is the predominant receptor theory and is closely related to the enzyme model of Michaelis and Menten. 

Clark developed occupancy theory in the 1920s and 1930s.23 He built his theory on the premise that a response (E) arises only when a receptor is occupied by a ligand, that is, from a ligand-receptor complex (RL). The response is directly proportional to [RL] (Equation 5.3). 

Intrinsic efficacy is the efficacy, or activity, per unit receptor. By including the idea of intrinsic efficacy, Stephenson explained how tissues with the same concentrations of a receptor can give rise to different dose-response graphs. The full results of Stephenson s contributions to occupancy theory are summarized in Equation 5.18.26... 

At the start of this section, we derived Equation 5.8 to model dose-response relationships. This equation is elegantly simple and essentially identical to the Michaelis-Menten equation from our studies on enzymes. Receptors, however, are more diverse and more complicated than enzymes. Clark s straightforward equation models few receptors accurately, and Stephenson s equation (5.18) has emerged as the best available description of occupancy theory. While Stephenson s additions may result in a more accurate model, the simplicity of Clark s original theory remains attractive. Many receptor studies still rely on Clark s model and work around its deficiencies as best as possible. 

While occupancy theory is far and away the most widely used model for describing dose-response curves, other theories do exist. One example is allosteric theory. At the center of allosteric theory, sometimes called the two-state model, is the idea that a receptor can exist in conformations that either cause a response (relaxed state) or do not cause a response (tensed state).29 These conformations, represented by T and R, are in equilibrium (Scheme 5.7). 

Another alternative to occupancy theory is rate theory. Rate theory was developed by Paton through examination of receptors that bind stimulants.30 Paton proposed that a response is caused by the act of binding, not the state of being bound or free (Scheme 5.8). This seemingly subtle difference shifts the theory away from KD and toward kon and fcoff, the rate constants of association and dissociation. Interestingly, at equilibrium, KD is equal to koa/kon (Equations 5.19-5.21). For this reason, occupancy and rate theory are closely related. 

Simple mathematical calculations by the first pharmacologists in the 1930s indicated that structurally specific drugs exert their action in very small doses and do not act on all molecules of the body but only on certain ones, those that constitute the drug receptors. For example, Clark [407] calculated that ouabain applied to the cells of the heart ventricle, isolated from the toad, would cover only 2.5% of the cellular surface. These observations prompted Clark [407,408] to apply the mathematical approaches used in enzyme kinetics to the effects of chemicals on tissues, and this formed the basis of the occupancy theory for drug-receptor interaction. Thus, pharmacological receptor models preceded accurate knowledge of receptors by many years. 

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