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Keywords:

  • Human 5-HT7 receptor;
  • adenylyl cyclase;
  • 5-CT;
  • [3H]-5-CT;
  • SB-269970-A;
  • guinea-pig;
  • rat;
  • hypothermia;
  • sleep;
  • EEG
  • The novel 5-HT7 receptor antagonist, SB-269970-A, potently displaced [3H]-5-CT from human 5-HT7(a) (pKi 8.9±0.1) and 5-HT7 receptors in guinea-pig cortex (pKi 8.3±0.2).

  • 5-CT stimulated adenylyl cyclase activity in 5-HT7(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 pKi determined from [3H]-5-CT binding studies.

  • 5-CT-stimulated 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 pKB (8.3±0.1) in good agreement with its antagonist potency at the human cloned 5-HT7(a) receptor and its binding affinity at guinea-pig cortical membranes.

  • 5-HT7 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 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.

  • 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.

  • 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