SB-236057-A: A Selective 5-HT1B Receptor Inverse Agonist

Abstract

5-HT_1B 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-HT_1B 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-HT_1B receptors (pK_i= 8.2) and displays 80 or more fold selectivity for the human 5-HT_1B receptor over other 5-HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5-HT_1B receptors SB-236057-A displayed inverse agonism (pA₂= 8.9) using [³⁵S]GTPγS binding, and silent antagonism (pA₂= 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-HT_1B subtype. It appears that acute 5-HT_1B receptor blockade, by virtue of increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.