S 15535 and WAY 100,635 antagonise 5-HT-stimulated [S-35]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 (K-i = 0.79 nM), similar to that of 5-HT (0.61 nM), (+/-)-8-hpdroxy-2-(di-n-propylamino)tetralin ((+/-)-8-OH-1-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 [S-35]GTP gamma S binding 3-fold (EC(50) = 15 nM) whereas (+/-)-8-OH-DPAT exhibited 73% efficacy relative to 5-HT (EC(50) = 6.0 nM). WAY 100,635 completely blocked 5-HT- and (+/-)-8-OH-DPAT-stimulated [S-35]GTP gamma S binding. Likewise, S 15535 antagonised 5-HT-stimulated [S-35]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 EC(50) values of 870 and 313 nM, respectively. However, unlike WAY 100,635, which by itself did not stimulate [S-35]GTP gamma S binding, S 15535 alone increased it by 34.7% relative to 5-HT (EC(50) = 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.