Discovery And Sar Studies Of 2-Alkyl-3-Phenyl-2,4,5,6,7,8-Hexahydropyra- Zolo[3,4-D]Azepines As 5-Ht7/2 Inhibitors Leading To The Identification Of A Clinical Candidate

We report here the synthesis and characterization of a dual 5-HT7 / 5-HT2 receptor antagonist 3-(4-Fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT7 and 5-HT2A receptor ligand having a pK(i) = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5HT(2A) and as an inverse agonist in an in vitro functional assay for 5-HT7. In a validated in vivo model for central 5HT(7) activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED50 = 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 similar to 27 ng/ml. In a validated in vivo model for central 5-HT2A activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED50 = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT2A receptor binding sites in the frontal cortex of the rat brain with an ED50 in good agreement with the ED50 value for central functional effect mediated by 5-HT2A receptor (ED50 = 0.8 mg/kg, p.o., 1 h).