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

Abstract

1. The novel 5-HT7 receptor antagonist, SB-269970-A, potently displaced [3H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9 ± 0.1) and 5-HT7 receptors in guinea-pig cortex (pK(i) 8.3 ± 0.2). 2. 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC50 7.5 ± 0.1) and SB-269970-A (0.03 - 1 μM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA2 (8.5 ± 0.2) for SB-269970-A agreed well with the pK(i) determined from [3H]-5-CT binding studies. 3. 5-CT-stimuluted adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC50 of 8.4 ± 0.2) was inhibited by SB-269970-A (0.3 μM) with a pK(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. 4. 5-HT7 receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. 5. SE-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 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested. 6. 5-CT (0.3 mg kg-1 i.p.) induced hypothermia in guinea-pigs was blocked by SB-269970-A (ED50 2.96 mg kg-1 i.p.) and the non-selective 5-HT7 receptor antagonist metergoline (0.3 3 mg kg-1 s.c.), suggesting a role for 5-HT7 receptor stimulation in 5-CT induced hypothermia in guinea-pigs. 7. 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.