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SB‐656104‐A, a novel selective 5‐HT 7 receptor antagonist, modulates REM sleep in rats
Author(s) -
Thomas David R,
Melotto Sergio,
Massagrande Mario,
Gribble Andrew D,
Jeffrey Phillip,
Stevens Alexander J,
Deeks Nigel J,
Eddershaw Peter J,
Fenwick Susan H,
Riley Graham,
Stean Tania,
Scott Claire M,
Hill Matthew J,
Middlemiss Derek N,
Hagan Jim J,
Price Gary W,
Forbes Ian T
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705290
Subject(s) - receptor , receptor antagonist , antagonist , 5 ht receptor , chemistry , medicine , endocrinology , hydrochloride , pharmacology , in vivo , 5 ht7 receptor , serotonin , biology , biochemistry , microbiology and biotechnology
(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‐HT 7 ) receptor antagonist, potently inhibited [ 3 H]‐SB‐269970 binding to the human cloned 5‐HT 7(a) (p K i 8.7±0.1) and 5‐HT 7(b) (p K i 8.5±0.2) receptor variants and the rat native receptor (p K i 8.8±0.2). The compound displayed at least 30‐fold selectivity for the human 5‐HT 7(a) receptor versus other human cloned 5‐HT receptors apart from the 5‐HT 1D receptor (∼10‐fold selective). SB‐656104‐A antagonised competitively the 5‐carboxamidotryptamine (5‐CT)‐induced accumulation of cyclic AMP in h5‐HT 7(a) /HEK293 cells with a pA 2 of 8.5. Following a constant rate iv infusion to steady state in rats, SB‐656104 had a blood clearance (CL b ) 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 t 1/2 of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 μ M , respectively. SB‐656104‐A produced a significant reversal of the 5‐CT‐induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5‐HT 7 receptor interaction in vivo (ED 50 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‐HT 7 receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5‐HT 7 receptors in the modulation of REM sleep.British Journal of Pharmacology (2003) 139 , 705–714. doi: 10.1038/sj.bjp.0705290