Kinetic Evaluation of Pharmacological Effects Based on Allosteric Coupling of the Benzodiazepine/γ-Aminobutyric Acid_A Receptor in the Brain

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A mathematical allosteric coupling model has been proposed to describe the process by which binding to the benzodiazepine/γ-aminobutyric acid (GABA) receptor complex initiates a biological response. The model states that the first receptors (benzodiazepine receptors) can diffuse independently in the plane of the membrane and reversibly associate with the second receptors (GABA receptors) to regulate their activity (induction of increased choloride ion flux due to the opening of the chloride ion channel). The ratio of agonist-bound to total GABA receptor density was defined to be directly proportional to the biological response in the model. The analysis makes the following assumptions : i) the binding affinity of agonists (muscimol or benzodiazepine) to the benzodiazepine receptor/GABA receptor complex is much greater than that to each receptor alone; ii) the double receptor-single agonist (benzodiazepine, muscimol or GABA) ternary complex binds to the other agonist with a high binding affinity as compared with that of each agonist to an agonist-free receptor complex; iii) benxodiazepine receptor-GABA receptor interaction is enhanced i the presence of each agonist; iv) the GABA receptor is desensitized after the binding of GABA agonist (GABA or muscimol) to the receptor. The modeling exercise shows that the benzodiazepine concentration required for half-maximal biological response is lower than that required for half-maximal receptor binding. In the case of the GABA agonist, a linear relationship between receptor occupancy and biolological response was observed. The degree of discrepancy between the two rofiles (receptor occupancy and biological response) concerning benzodiazepine concentration dependency and time dependency increased with a decrease in the dissociation constants based on the benodizepine receptor-GABA receptor interaction. This model offers a simple explanation for discrepancies between the receptor occupancy-concentration profile of benzodiazepine and the biological response-concentration curve that are often observed in vivo and/or in vitro.
公益社団法人日本薬学会の論文
1991-07-25

Kinetic Evaluation of Pharmacological Effects Based on Allosteric Coupling of the Benzodiazepine/γ-Aminobutyric Acid_A Receptor in the Brain

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