SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats

(6-((R)-2-{2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl}-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT7) receptor antagonist, potently inhibited [3H]-SB-269970 binding to the human cloned 5-HT7(a) (pKi 8.7±0.1) and 5-HT7(b) (pKi 8.5±0.2) receptor variants and the rat native receptor (pKi 8.8±0.2). The compound displayed at least 30-fold selectivity for the human 5-HT7(a) receptor versus other human cloned 5-HT receptors apart from the 5-HT1D receptor (∼10-fold selective). SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT7(a)/HEK293 cells with a pA2 of 8.5. Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CLb) of 58±6 ml min−1 kg−1 and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg−1), the compound displayed a t1/2 of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 μM, respectively. SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT7 receptor interaction in vivo (ED50 2 mg kg−1). SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg−1 i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg−1 i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. In summary, SB-656104-A is a novel 5-HT7 receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT7 receptors in the modulation of REM sleep. British Journal of Pharmacology (2003) 139, 705–714. doi:10.1038/sj.bjp.0705290