SB‐236057‐A: A Selective 5‐HT(1B) Receptor Inverse Agonist

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 (pA(2)= 8.9) using [(35)S]GTPγS 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 [(3)H]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.