title: SB-236057-A: a selective 5-HT1B receptor inverse agonist.
abstract: 5-HT1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5-HT1B receptor inverse agonist, SB-236057-A (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro (furo[2,3-f]indole-3,4'-piperidine) hydrochloride). SB 236057-A has been shown to have high affinity for human 5-HT1B receptors (pK(i) = 8.2) and displays 80 or more fold selectivity for the human 5-HT1B receptor over other 5-HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5-HT1B receptors SB-236057-A displayed inverse agonism (pA(2) = 8.9) using [(35)S]GTPgammaS binding, and silent antagonism (pA(2) = 9.2) using cAMP accumulation. SB-236057-A also acted as an antagonist at the 5-HT terminal autoreceptor as measured by [3H]5-HT release from electrically stimulated guinea pig and human cortical slices. In the guinea pig, pharmacokinetic analysis demonstrated that SB-236057-A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints. In vivo microdialysis studies demonstrated that SB-236057-A is an antagonist in the guinea pig cortex but has no effect on extracellular 5-HT levels per se. In contrast, SB-236057-A increased extracellular 5-HT levels in the guinea pig dentate gyrus. This increase in 5-HT release was comparable to that observed after 14 days of paroxetine administration. SB-236057-A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5-HT autoreceptor is of the 5-HT1B subtype. It appears that acute 5-HT1B receptor blockade, by virtue of increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.
authors.affiliation: Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Ave., Harlow, Essex, CM19 5AW, UK. Claire_Roberts-1@gsk.com
authors.forename: C
authors.initials: C
authors.lastname: Roberts
authors.forename: J
authors.initials: J
authors.lastname: Watson
authors.forename: G W
authors.initials: GW
authors.lastname: Price
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007035:Hypothermia / Q000378:metabolism; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017551:Microdialysis; D017374:Paroxetine / Q000494:pharmacology; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D017660:Autoreceptors; D000242:Cyclic AMP; D007211:Indoles; D017374:Paroxetine; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C470302:HTR1B protein, human; C121558:SB 236057