Characterization of SB‐269970‐A, a selective 5‐HT7 receptor antagonist

The novel 5‐HT 7 receptor antagonist, SB‐269970‐A, potently displaced [ 3 H]‐5‐CT from human 5‐HT 7(a) (p K i 8.9±0.1) and 5‐HT 7 receptors in guinea‐pig cortex (p K i 8.3±0.2). 5‐CT stimulated adenylyl cyclase activity in 5‐HT 7(a) /HEK293 membranes (pEC 50 7.5±0.1) and SB‐269970‐A (0.03–1 μ M ) inhibited the 5‐CT concentration‐response with no significant alteration in the maximal response. The pA 2 (8.5±0.2) for SB‐269970‐A agreed well with the p K i determined from [ 3 H]‐5‐CT binding studies. 5‐CT‐stimulated adenylyl cyclase activity in guinea‐pig hippocampal membranes (pEC 50 of 8.4±0.2) was inhibited by SB‐269970‐A (0.3 μ M ) with a p K B (8.3±0.1) in good agreement with its antagonist potency at the human cloned 5‐HT 7(a) receptor and its binding affinity at guinea‐pig cortical membranes. 5‐HT 7 receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB‐269970‐A was CNS penetrant (steady‐state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min −1 kg −1 ). Following a single dose (3 mg kg −1 ) SB‐269970 was detectable in rat brain at 30 (87 n M ) and 60 min (58 n M ). In guinea‐pigs, brain levels averaged 31 and 51 n M respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested. 5‐CT (0.3 mg kg −1 i.p.) induced hypothermia in guinea‐pigs was blocked by SB‐269970‐A (ED 50 2.96 mg kg −1 i.p.) and the non‐selective 5‐HT 7 receptor antagonist metergoline (0.3–3 mg kg −1 s.c.), suggesting a role for 5‐HT 7 receptor stimulation in 5‐CT induced hypothermia in guinea‐pigs. SB‐269970‐A (30 mg kg −1 ) administered at the start of the sleep period, significantly reduced time spent in Paradoxical Sleep (PS) during the first 3 h of EEG recording in conscious rats. British Journal of Pharmacology (2000) 130 , 539–548; doi: 10.1038/sj.bjp.0703357