ID: ALA4673280
Journal: Bioorg Med Chem Lett
Title: Discovery and SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as 5-HT inhibitors leading to the identification of a clinical candidate.
Authors: Dvorak CA,Rudolph DA,Nepomuceno D,Dvorak L,Lord B,Fraser I,Bonaventure P,Lovenberg T,Carruthers NI
Abstract: We report here the synthesis and characterization of a dual 5-HT / 5-HT receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT and 5-HT receptor ligand having a pK = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT and as an inverse agonist in an in vitro functional assay for 5-HT. In a validated in vivo model for central 5-HT activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~27 ng/ml. In a validated in vivo model for central 5-HT activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT receptor binding sites in the frontal cortex of the rat brain with an ED in good agreement with the ED value for central functional effect mediated by 5-HT receptor (ED = 0.8 mg/kg, p.o., 1 h).
CiteXplore: 33171218
DOI: 10.1016/j.bmcl.2020.127669
Patent ID: ┄