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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2000-8-1
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pubmed:abstractText |
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.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-10052959,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-10369478,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-10498847,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-10669560,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-1309231,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-3500757,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-4202581,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-7518496,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-7601444,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-7647964,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-7838138,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-8398139,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-8882587,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-9084407,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-9175892,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-9274976,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/10821781-9836301
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0007-1188
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pubmed:author |
pubmed-author:BromidgeS MSM,
pubmed-author:DeeksN JNJ,
pubmed-author:HaganJ JJJ,
pubmed-author:JeffreyPP,
pubmed-author:LovellP JPJ,
pubmed-author:MedhurstA DAD,
pubmed-author:MiddlemissD NDN,
pubmed-author:PiperDD,
pubmed-author:PriceG WGW,
pubmed-author:RileyG JGJ,
pubmed-author:SmithM IMI,
pubmed-author:SteadBB,
pubmed-author:ThomasD RDR,
pubmed-author:UptonNN
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pubmed:issnType |
Print
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pubmed:volume |
130
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
539-48
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:10821781-Adenylate Cyclase,
pubmed-meshheading:10821781-Animals,
pubmed-meshheading:10821781-Body Temperature,
pubmed-meshheading:10821781-Cerebral Cortex,
pubmed-meshheading:10821781-Guinea Pigs,
pubmed-meshheading:10821781-Hippocampus,
pubmed-meshheading:10821781-Humans,
pubmed-meshheading:10821781-Male,
pubmed-meshheading:10821781-Membranes,
pubmed-meshheading:10821781-Phenols,
pubmed-meshheading:10821781-RNA, Messenger,
pubmed-meshheading:10821781-Rats,
pubmed-meshheading:10821781-Rats, Sprague-Dawley,
pubmed-meshheading:10821781-Receptors, Serotonin,
pubmed-meshheading:10821781-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:10821781-Serotonin Antagonists,
pubmed-meshheading:10821781-Sleep,
pubmed-meshheading:10821781-Sleep Stages,
pubmed-meshheading:10821781-Sulfonamides
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pubmed:year |
2000
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pubmed:articleTitle |
Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist.
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pubmed:affiliation |
Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW.
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pubmed:publicationType |
Journal Article
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