SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'methyl-4'-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): a novel, potent and selective 5-HT1B receptor antagonist.
SB-616234-A possesses high affinity for human 5-HT1B receptors stably expressed in Chinese hamster ovary (CHO) cells (pKi 8.3+/-0.2), and is over 100-fold selective for a range of molecular targets except h5-HT1) receptors (pKi 6.6+/-0.1). Similarly, affinity (pKi) for rat and guinea pig striatal 5-HT1B receptors is 9.2+/-0.1. In [35S]-GTPgammaS binding studies in the human recombinant cell line, SB-616234-A acted as a high affinity antagonist with a pA2 value of 8.6+/-0.2 whilst providing no evidence of agonist activity in this system. In [35S]-GTPgammaS binding studies in rat striatal membranes, SB-616234-A acted as a high affinity antagonist with an apparent pKB of 8.4+/-0.5, again whilst providing no evidence of agonist activity in this system. SB-616234-A (1 microM) potentiated electrically stimulated [3H]-5-HT release from guinea pig and rat cortical slices (S2/S1) ratios of 1.8 and 1.6, respectively). SB-616234-A (0.3-30 mg kg(-1) p.o.) caused a dose-dependent inhibition of ex vivo [3H]-GR125743 binding to rat striatal 5-HT1B receptors with an ED50 of 2.83+/-0.39 mg kg(-1) p.o. Taken together these data suggest that SB-616234-A is a potent and selective 5-HT(1B) autoreceptor antagonist that occupies central 5-HT1B receptors in vivo following oral administration.
Department of Biology, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK. claire.m.scott@gsk.com
Claire
C
Scott
Christopher J
CJ
Langmead
Kirsten L
KL
Clarke
Paul
P
Wyman
Paul W
PW
Smith
Kathryn R
KR
Starr
Lee A
LA
Dawson
Gary W
GW
Price
James J
JJ
Hagan
Jeannette
J
Watson
D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002540:Cerebral Cortex / Q000166:cytology; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010069:Oxadiazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D012701:Serotonin / Q000493:pharmacokinetics; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics
D007211:Indoles; D010069:Oxadiazoles; D010879:Piperazines; C513705:SB-616234-A; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D013460:Sulfur Isotopes; D014316:Tritium; C090701:GR 127935; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate)