The dissociation rate of unlabelled drugs from receptor sites: a poorly investigated, yet important aspect in receptor research. Studies on the serotonin-S2 receptor.
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 pharmacokinetic 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.
Leysen
J E
JE
Department of Biochemical Pharmacology, Janssen Pharmaceutica, Beerse, Belgium.
Gommeren
W
W
Van Gompel
P
P
D000818:Animals; D001667:Binding, Competitive; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D007650:Ketanserin / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism*
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013134:Spiperone; D007650:Ketanserin