Characterisation of the selective 5-HT1B receptor antagonist SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): in vivo neurochemical and behavioural evidence of anxiolytic/antidepressant activity.

Abstract

The 5-HT1B receptor has attracted significant interest as a potential target for the development of therapeutics for the treatment of affective disorders such as anxiety and depression. Here we present the in vivo characterisation of a novel, selective and orally bioavailable 5-HT1B receptor antagonist, SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride). SB-616234-A reversed the 5-HT1/7 receptor agonist, SKF-99101H-induced hypothermia in guinea pigs in a dose related manner with an ED50 of 2.4 mg/kg p.o. Using in vivo microdialysis in freely moving guinea pigs, SB-616234-A (3-30 mg/kg p.o.) caused a dose-related increase in extracellular 5-HT in the dentate gyrus. Evaluation of antidepressant- and anxiolytic-like effects of this 5-HT1B receptor antagonist was performed in a variety of models and species. SB-616234-A produced a decrease in immobility time in the mouse forced swim test; an effect suggestive of antidepressant activity. Furthermore, SB-616234-A produced dose-related anxiolytic effects in both rat and guinea pig maternal separation-induced vocalisation models with an ED50 of 1.0 and 3.3 mg/kg i.p., respectively (vs fluoxetine treatment ED50 = 2.2 mg/kg i.p. in both species). Also a significant reduction in posturing behaviours was observed in the human threat test in marmosets; an effect indicative of anxiolytic activity. In summary, SB-616234-A is a novel, potent and orally bioavailable 5-HT1B receptor antagonist which exhibits a neurochemical and behavioural profile that is consistent with both anxiolytic- and antidepressant-like activity in a variety of species. Taken together these data suggest that SB-616234-A may have therapeutic efficacy in the treatment of affective disorders.

• Authors: Lee A Dawson, Zoë A Hughes, Kathryn R Starr, James D Storey, Letizia Bettelini, Fabrizio Bacchi, Roberto Arban, Alessandro Poffe, Sergio Melotto, James J Hagan, Gary W Price
• Journal: Neuropharmacology (Neuropharmacology) Vol. 50 Issue 8 Pg. 975-83 (Jun 2006) ISSN: 0028-3908 [Print] England
• PMID: 16581092 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Anxiety Agents
• Antidepressive Agents
• Indoles
• Piperazines
• SB-616234-A
• Serotonin Antagonists
• SKF 99101H
• Serotonin

Topics

• Analysis of Variance
• Animals
• Anti-Anxiety Agents (pharmacology)
• Antidepressive Agents (pharmacology)
• Behavior, Animal (drug effects)
• Brain Chemistry (drug effects)
• Callithrix
• Dose-Response Relationship, Drug
• Drug Interactions
• Guinea Pigs
• Hypothermia (chemically induced, drug therapy)
• Immobility Response, Tonic (drug effects)
• Indoles (pharmacology, toxicity)
• Male
• Motor Activity (drug effects)
• Piperazines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Serotonin (metabolism)
• Serotonin Antagonists (pharmacology)
• Swimming (psychology)
• Time Factors
• Vocalization, Animal (drug effects)