Receptors rate theory

The rate theory of Paton, as modified by Paton and Rang, rejects the assumption that the response is proportional to the number of occupied receptors, and instead proposes a relationship of response to the rate of drug-receptor complex formation. According... 

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. 

Rate theory does successfully model the behavior of many receptors. It can also be adapted to accommodate partial agonists and antagonists. Determining kon and fcoff requires more experimental effort than determining KV). 

This mechanism was defined later by Bush [6] as the blocking mechanism. Bush s classification is based on Raton s rate theory of drug action [181]. Raton suggested that a pharmacological effect depends not upon the number of individual drug-receptor combinations but upon the rate, of drug-receptor occupation. He assumes that receptor... 

The primary factor delineating occupancy and rate theory seemed to be the dissociation rate constant. Thus, if this factor was large, the ligand was an agonist if the factor was small, reducing the quantal response to receptor occupancy, the ligand functioned as an an-... 

Receptor inactivation theory, initially proposed by Gosselin in 1977 has been widely disseminated by Kenakin (35)and to some degree is based on the two-state model originally proposed by Katz and Thesleff (41) for ion channels, specifically the Torpedo nicotinic receptor. where the multimeric receptor exists in active and inactive states, with ligand binding altering the equilibrium between these two states. Receptor inactivation theory reflects a synthesis of both occupancy and rate theories providing an alternative consideration for the study of the RL interaction. 

The efficacy of the peptide is lower than 1 when tested on several preparations (Table 1). Furthermore, dose-effect curves are curves with an optimum which characterize partial agonists. The dissociation of angiotensin from the receptor site is slow on isolated preparations it can be accelerated either by incubation with angiotensinase or by repeated washing (Fig. 3). Such observations are interpreted in terms of rate theory of drug action (see Sect B. Chap. 6). 

In direct opposition to the occupation theory, the rate theory assumes that an occupied receptor is actually an eliminated one. Obviously, when studying only the equilibrium state, no evidence can be found corroborating or disproving either of these two concepts. Only the reaction course at the start of the drug-receptor interaction might solve the problem as to whether in a certain case the occupation or rate theory is more correct. Figure 14 shows the overshoot and the fade postulated by the rate theory. 

According to the occupation theory, the amount of occupied receptors is important, the rate of drug-receptor complex formation having no primary importance. According to the rate theory, the opposite is true. 

As early as 1848, it had been suggested that sensory receptors transduce only one sensation, independent of the manner of stimulation. Behavioral experiments tend to support this theory. In 1919, Renqvist proposed that the initial reaction of taste stimulation takes place on the surface of the taste-cell membrane. The taste surfaces were regarded as colloidal dispersions in which the protoplasmic, sensory particles and their components were suspended in the liquor or solution to be tested. The taste sensation would then be due to adsorption of the substances in the solution, and equal degrees of sensation would correspond to adsorption of equal amounts. Therefore, the rate of adsorption of taste stimulants would be proportional to the total substances adsorbed. The phenomenon of taste differences between isomers was partly explained by the assumption that the mechanism of taste involves a three-dimensional arrangement for example, a layer of fatty acid floating on water would have its carboxylic groups anchored in the water whereas the long, hydrocarbon ends would project upwards. 

In 1976 Martin proposed the theory that there are three subtypes of opioid receptor on the basis of behavioural studies using a chronic spinal dog model which revealed that the opioids morphine (mu) (1), ketazocine (kappa) (2) and A-allylnormetazocine (SKF 10047) (4) (sigma) had different effects on respiration, heart rate and locomotor activity [13]. Furthermore, these ligands were unable to replace each other to prevent withdrawal symptoms in dogs that had been chronically treated with one of the compounds. 

Bimolecular processes are very common in biological systems. The binding of a hormone to a receptor is a bimolecular reaction, as is substrate and inhibitor binding to an enzyme. The term bimolecular mechanism applies to those reactions having a rate-limiting step that is bimolecular. See Chemical Kinetics Molecularity Reaction Order Elementary Reaction Transition-State Theory... 

Extensions of receptor modeling theory to light extinction and to reactive chemical compounds require introduction of rate process concepts. 

Paton, W. D. M. A Theory of Drug Action Based on the Rate of Drug-Receptor Combination. Proc. R. Soc. London, Ser. B. 1961,154, 21-69. 

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