S 15535 and WAY 100,635 antagonise 5-HT-stimulated [35S]GTP gamma S binding at cloned human 5-HT1A receptors.
In Chinese hamster ovary (CHO) cells expressing cloned human 5-HT1A receptors, S 15535 (4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine) exhibited high affinity (Ki = 0.79 nM), similar to that of 5-HT (0.61 nM), (+/-)-8-hydroxy-3-(di-n-propylamino)tetralin ((+/-)-8-OH-DPAT; 0.58 nM) and N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N- (2-pyridinyl)cyclo-hexanecarboxamide (WAY 100.635; 0.56 nM). In these cells, 5-HT stimulated [35S]GTP gamma S binding 3-fold (EC50 = 15 nM) whereas (+/-)-8-OH-DPAT exhibited 73% efficacy relative to 5-HT (EC50 = 6.0 nM). WAY 100.635 completely blocked 5-HT- and (+/-)-8-OH-DPAT-stimulated [35S]GTP gamma S binding. Likewise, S 15535 antagonised 5-HT-stimulated [35S]GTP gamma S binding, reducing it to 30.1% of control values. S 15535 (100 nM) also shifted the 5-HT and (+/-)-8-OH-DPAT stimulation curves to the right, to EC50 values of 870 and 313 nM, respectively. However, unlike WAY 100.635, which by itself did not stimulate [35S]GTP gamma S binding, S 15535 alone increased it by 34.7% relative to 5-HT (EC50 = 5.8 nM). In conclusion, S 15535 antagonises the stimulation of 5-HT1A receptors by 5-HT, whilst itself exerting weak partial agonist activity at these sites.
Newman-Tancredi
A
A
Department of Psychopharmacology, Institut de Recherches Servier, Croissy-sur-Seine, Paris, France.
Chaput
C
C
Verrièle
L
L
Millan
M J
MJ
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013268:Stimulation, Chemical; D014316:Tritium
D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014316:Tritium; C079549:4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin