Receptors theories

Clark s next step formed the basis of receptor theory by applying chemical laws to systems of infinitely greater complexity [4]. It is interesting to note the scientific atmosphere in which Clark published these ideas. The dominant ideas between 1895 and 1930 were based on theories such as the law of phasic variation essentially stating that certain phenomena occur frequently. Homeopathic theories like the Amdt-Schulz law and... 

It is amazing to note that complex processes such as drug binding to protein, activation of cells, and observation of syncytial cellular response should apparently so closely follow a model based on these simple concepts. This was not lost on A. J. Clark in his treatise on drug receptor theory The Mode of Action of Drugs on Cells [4] ... 

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. 

From the time of A. J. Clark until the late 1970s, receptor models have been refined to describe drug affinity and efficacy. These ideas are collectively referred to as classical receptor theory. 

The observation that receptors can demonstrate spontaneous activity necessitated elements of ion two-state theory to be incorporated into receptor theory. 

MacKay, D. (1977). A critical survey of receptor theories of drag action. In Kinetics of drug action, edited by J. M. Van Rossum, pp. 255—322. Springer-Verlag, Berlin. 

Furchgott, R. F. (1972). The classification of adrenoreceptors (adrenergic receptors) An evaluation from the standpoint of receptor theory. In Handbook of experimental pharmacology, catecholamines, Vol. 33, edited by H. Blaschko and E. Muscholl, pp. 283—335. Springer-Verlag, Berlin. 

By utilizing complete dose-response curves, the method devised by Barlow, Scott, and Stephenson [9] can be used to measure the affinity of a partial agonist. Using null procedures, the effects of stimulus-response mechanisms are neutralized and receptor-specific effects of agonists are isolated. This method, based on classical or operational receptor theory, depends on the concept of equiactive concentrations of drug. Under these circumstances, receptor stimuli can be equated since it is assumed that equal responses emanate from equal stimuli in any given system. An example of this procedure is given in Section 12.2.1. 

In terms of classical receptor theory, equiactive responses to an agonist are compared in the control situation ([A]) and after irreversible inactivation of a fraction of the receptors ([A7]). Assume that after alkylation the remaining receptors equal a fraction q ... 

In terms of classical receptor theory—where response is a hyperbolic function of stimulus (Response = Stimulus/ (Stimulus 4- [3), [3 is a transducer function reflecting the efficiency of the stimulus-response mechanism of the system), and stimulus is given by Stimulus = [A] e/([A] + KA) (e is the efficacy of the agonist)— Response is given by... 

Boeynaems, J. M., ancl Dumont, J. E. (1980). Outlines of receptor theory. Elsevier/North-Hollancl, Amsterdam. 

In general, receptor theory uses indirect mathematical models to estimate descriptors of drug effect. These descriptors still must be used with the proviso that biological systems may still modify drug effect in a system-dependent manner and thus predictions of therapeutic effect must be made with caution across different systems. 

Kenakin T (2004) Principles receptor theory in phar macology. Trends Pharmacol Sci 25 186—192... 

Samama, P., Cotecchia, S., Costa, T., and Lefkowitz, R. J., A mutation-induced activated state of the p2-adrenergic receptor extending the ternary complex model, J. Biol. Chem., 268, 4625-4636, 1993. Stephenson, R. P., A modification of receptor theory, Br. J. Pharmacol., 11, 379-393, 1956. 

Classical receptor theory suggests that the response seen will be proportional to the percentage of receptors occupied, although this is not always the case. 

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