SB-236057, a selective 5-HT1B receptor inverse agonist, blocks the 5-HT human terminal autoreceptor.
A novel compound, SB-236057 (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl- 4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperid ine]) has been shown to have high affinity for human 5-hydroxytryptamine1B (5-HT1B) receptors (pKi = 8.2) and displays over 75 or more-fold selectivity for the human 5-HT1B receptor over other 5-HT receptors, including the human 5-HT1D receptor, and a range of other receptors, ion channels and enzymes. In functional studies using [35S]GTPgammaS binding, SB-236057 displayed negative intrinsic activity (pEC50 = 8.0) at human 5-HT1B receptors stably expressed in Chinese Hamster Ovary (CHO) cells and caused a rightward shift of agonist concentration response curves consistent with competitive antagonism (pA2 = 8.9). SB-236057 potentiated [3H]5-HT release from electrically stimulated guinea pig or human cortical slices. SB-236057 also abolished the inhibitory effect of exogenously superfused 5-HT on electrically-stimulated release from slices of the guinea pig cortex. These studies using SB-236057 confirm that, in both the guinea pig and human cerebral cortex, the terminal 5-HT autoreceptor is of the 5-HT1B subtype.
Middlemiss
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DN
Department of Neurosciences, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
Göthert
M
M
Schlicker
E
E
Scott
C M
CM
Selkirk
J V
JV
Watson
J
J
Gaster
L M
LM
Wyman
P
P
Riley
G
G
Price
G W
GW
D000818:Animals; D017660:Autoreceptors / Q000187:drug effects*; D001665:Binding Sites; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism*; D006224:Cricetinae; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000145:classification* / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D017660:Autoreceptors; D007211:Indoles; D011725:Pyridines; D011985:Receptors, Serotonin; C121558:SB 236057; D012702:Serotonin Antagonists; D012701:Serotonin