The Dissociation Rate of Unlabelled Drugs from Receptor Sites: A Poorly Investigated, Yet Important Aspect in Receptor Research. Studies on the Serotonin-S₂ Receptor

Abstract

The labelling by ³H-spiperone of serotonin-S₂ receptors in rat frontal cortex tissue adsorbed to glass fibre filters was investigated. For 12 unlabelled serotonin antagonists the dissociation time from serotonin-S₂ receptors was measured using rat frontal cortex tissue preparations adsorbed to glass fibre filters. The dissociation half-time varied from 4.8 min for pipamperone to 160 min for ritanserin. The drug-receptor dissociation time was not related to a particular class of chemical structure, or to the lipophilicity or the acid dissociation constant of the drugs. The essential requirement of experimental determination of the drug-receptor dissociation time for each drug individually is illustrated. The possible applications of the knowledge of the drug-receptor dissociation time in in vitro and in vivo receptor studies, in pharmacological and pharmaco-kinetic studies and in drug design and receptor modelling is discussed. For various serotonin-S₂ antagonists, the type of inhibition produced by the drug on ³H-ketanserin binding to serotonin-S₂ receptors was determined using suspensions of rat frontal cortical tissue. The observed patterns of inhibition were clearly related to the drug-receptor dissociation times: rapidly dissociating drugs produced competitive inhibition, drugs with dissociation half-times between 15-30 min produced mixed type inhibition, and the very slowly dissociating ritanserin produced non-competitive inhibition.