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

CNS Drug Rev. Winter 2001;7(4):433-44. doi: 10.1111/j.1527-3458.2001.tb00209.x.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Autoreceptors / drug effects
  • Brain / metabolism
  • Cyclic AMP / metabolism
  • Humans
  • Hypothermia / metabolism
  • Indoles / adverse effects
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Microdialysis
  • Paroxetine / pharmacology
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Radioligand Assay
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT1D
  • Receptors, Serotonin / drug effects*
  • Serotonin / metabolism
  • Serotonin Antagonists / adverse effects
  • Serotonin Antagonists / pharmacokinetics
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / adverse effects
  • Serotonin Receptor Agonists / pharmacokinetics
  • Serotonin Receptor Agonists / pharmacology*
  • Serotonin Uptake Inhibitors / pharmacology


  • Autoreceptors
  • HTR1B protein, human
  • Indoles
  • Pyridines
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT1D
  • Receptors, Serotonin
  • SB 236057
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Serotonin
  • Paroxetine
  • Cyclic AMP