<i>Receptor Mechanisms</i> Fourth Gaddum Memorial Lecture, School of Pharmacy, University of London, January 1973

The problems of constructing steady-state models of drug-receptor interaction in vivo are reviewed. The interrelation between drugs acting in a nonaqutous environment and their structural requirements at receptor sites is explored. In the proposed model, for given classes of receptors, the highly perfused lean tissue organs are considered as composed of two primary phases, aqueous and mcmbranal where the receptors are embedded in the membrane phase. It is shown that, for a given binding constant referenced to the membrane lipoidal phase, the infusion concentration of a drug will be dependent on its partitioning effect into the lipoidal region, the relevant binding conformer fraction in this phase, and the average rate of elimination of the compound from the aqueous compartment. The relation of the model under restricted conditions to the Hansch-Fujita equation is considered, and the limits of applicability of these models are defined.Data on antagonists of the j3-adrenergic receptor are examined in the context of the steady-state model using the Hansch-Fujita equation under the defined conditions. Binding constants of the drugs referenced to the lipoidal phase at the cardiac site are shown to be consistent with those obtained in v i m and at the isolated membrane level. The model indicates that pulmonary and cardiac responses appear controlled by identical j3 receptors. A major component of variation in the vascular response can be attributed to pharmacokinetic effects. While the conformational flexibility of the drugs examined is restricted, such evidence must be considered in any subclassification of @-adrenergic receptors.It is suggested that biological models have a clear path for development from the physicochemical viewpoint.

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Partial agonism of cardiac β-adrenoceptor Blocking Agents and Competitive Conformer-Receptor Occupancy

Davies¹,

Smith²

2009

Int. J. Quantum Chem.

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Thc possibility that diffcrcnt conformations of a drug may control agonist and antagonist action upon biological receptors is explored in terms of a Competitive conformer-rcceptor occupancy model. Partial agonism is shown to bc a function of four parameters. the binding constants of the agonist and antagonist conformers. and the relativc populations of the conformers. Thc relation to Michaelis-Mcntcn formalism is defined. Application of thc model to thc partial agonist activity of phenoxypropanolamines on cardiac g-adrenoccptors suggests that a similar conformation of the compounds controls both agonist and antagonist action on the rcccptor. but thc agonist conforniation has ii marked additional conformational restriction and a displacement within the receptor to initiatc ii stimulatory response.

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Receptor Mechanisms Fourth Gaddum Memorial Lecture, School of Pharmacy, University of London, January 1973

Cited by 38 publications

References 77 publications

Junctional Transmission I. Postsynaptic Mechanisms

Junctional Transmission I. Postsynaptic Mechanisms

A steady-state model of drug-receptor interaction in vivo applied to antagonists of the β-adrenergic receptor

Partial agonism of cardiac β-adrenoceptor Blocking Agents and Competitive Conformer-Receptor Occupancy

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