AT-1015, a newly synthesized 5-HT2 receptor antagonist, dissociates slowly from the 5-HT2 receptor sites in rabbit cerebral cortex membrane.
The purpose of this study was to investigate the association and dissociation kinetics of [3H]AT-1015 from 5-HT2 receptors in rabbit cerebral cortex membranes using a radioligand binding assay method and to make a comparison with those of [3H]ketanserin binding. Scatchard analysis of [3H]AT-1015 binding in rabbit cerebral cortex membranes indicated the existence of a single class of binding sites (dissociation constant, Kd = 2.18 nM). The specific binding of [3H]AT-1015 increased slowly with time and the association rate constant of [3H]AT-1015 binding (k1 = 0.1229 min-1 nM-1) was two times slower than that of [3H]ketanserin binding (k1 = 0.2451 min-1 nM-1). The dissociation rate constant of [3H]AT-1015 binding (t 1/2 = 37.03 min) was six times slower than that of [3H]ketanserin binding (t 1/2 = 6.29 min), when the addition of excess unlabelled ligands were AT-1015 and ketanserin, respectively. The dissociation rate constant of [3H]AT-1015 was slowed to a greater degree (t 1/2 = 163.40 min and t 1/2 = 198.12 min) by the addition of ketanserin and sarpogrelate as excess unlabelled ligands than was that of [3H]ketanserin (t 1/2 = 17.76 min and t 1/2 = 18.45 min) by the addition of AT-1015 and sarpogrelate as an excess unlabelled ligand, respectively. These findings on the dissociation kinetics of [3H]AT-1015 have confirmed and supported previously reported evidence of the slower dissociation of AT-1015 from 5-HT2 receptors.
Department of Pharmacology, Niigata College of Pharmacy, 5-13-2 Kamishinei-cho, Niigata 950-2081, Japan.
Mamunur
M
Rashid
Masatomo
M
Watanabe
Mikio
M
Nakazawa
Takafumi
T
Nagatomo
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002462:Cell Membrane; D002540:Cerebral Cortex / Q000502:physiology; D007540:Isonipecotic Acids / Q000493:pharmacokinetics*; D007650:Ketanserin / Q000493:pharmacokinetics*; D007700:Kinetics; D011817:Rabbits; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics*
D007540:Isonipecotic Acids; C411870:N-(2-(4-(5H-dibenzo(a,d)cyclohepten-5-yliden)piperidino)ethyl)-1-formyl-4-piperidinecarboxamide; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007650:Ketanserin