title: Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist.
abstract: The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(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 microM) 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 pK(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 microM) 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. 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 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 (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.
authors.affiliation: Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: G W
authors.initials: GW
authors.lastname: Price
authors.forename: P
authors.initials: P
authors.lastname: Jeffrey
authors.forename: N J
authors.initials: NJ
authors.lastname: Deeks
authors.forename: T
authors.initials: T
authors.lastname: Stean
authors.forename: D
authors.initials: D
authors.lastname: Piper
authors.forename: M I
authors.initials: MI
authors.lastname: Smith
authors.forename: N
authors.initials: N
authors.lastname: Upton
authors.forename: A D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: G J
authors.initials: GJ
authors.lastname: Riley
authors.forename: P J
authors.initials: PJ
authors.lastname: Lovell
authors.forename: S M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: D R
authors.initials: DR
authors.lastname: Thomas
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D008566:Membranes / Q000378:metabolism; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects; D012894:Sleep Stages / Q000187:drug effects; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D010636:Phenols; D012333:RNA, Messenger; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D000262:Adenylyl Cyclases