Effects of conformationally restricted 4-piperazinyl-10H-thienobenzodiazepine neuroleptics on central dopaminergic and cholinergic systems

Abstract

The levels of antidopaminergic and anticholinergic activities of neuroleptics, 4-piperazinyl-10H-thienobenzodiazepines, are modulated by imposing steric impedence to the piperazine ring. The optimum situation in favor of the anticholinergic action is reached in compound 5, 2,3-dimethyl-7-fluoro-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, where a maximum activity (equivalent to hyoscine), as measured by the [3H]QNB receptor binding assay, is obtained. The structure-activity relationships found highlight the importance of certain spatial dispositions of the distal piperazine nitrogen (electron lone pair) with respect to the tricyclic system. The evidence for molecular topography of these compounds is presented from X-ray, NMR, and other physical data. The conformational aspects for correspondence to the relevant receptors are discussed.

Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects

“…Table 2 illustrates the major potential tetracyclic antipsychotics in their developmental stages, including a brief summary of their pre-clinical studies during the last decade. These tetracyclic compounds possess a basic piperazine ring containing a distal nitrogen, which is essential for the receptor interactions and the efficacy of antipsychotic drugs (Chakrabarti et al 1982). 6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl 4H-3-thia-4,9-diaza-benzo [f]azulene (FMPD), 660864-42-6, 660865-03-2, and 221059-44-5 show high potency for dopaminergic receptors.…”

“…Table 2 illustrates the major potential tetracyclic antipsychotics in their developmental stages, including a brief summary of their pre‐clinical studies during the last decade. These tetracyclic compounds possess a basic piperazine ring containing a distal nitrogen, which is essential for the receptor interactions and the efficacy of antipsychotic drugs (Chakrabarti et al. 1982).…”

Isolation, Identification, and Synthesis of Two Oxidative Degradation Products of Olanzapine (LY170053) in Solid Oral Formulations

“…This leaves only the assignment of the N‐methyl piperazine substructure to complete the molecule; however, while the presence of the N‐methyl piperazine ring is indicated by the mass spectral data (see below) not all of the resonances were observed for the N‐methyl piperazine substructure in the NMR spectra. The absence of some of the N‐methyl piperazine resonances has been observed for other olanzapine‐related compounds and has been ascribed to a broadening of the resonances due to a combination of rotation around the central amidino CN bond of >NCN, piperazine chair–chair interconversion, and nitrogen inversion 2. In order to sharpen the broadened NMR resonances, the free base of 1 was prepared by dissolving in aqueous base and extracting with chloroform.…”

2-(2-Nitroanilino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile

“…Amongst these appplications, are neuroleptics activities, as found for a series of thienobenzodiazepines (Chakrabarti et al, 1982;Calligaro et al, 1997;Nikolakopoulos et al, 2006). In this work, we report the structure of the title compound prepared by the reaction of 2-amino-5,6,7, 8-tetrahydro-4H-ciclohepta[b]thiophene-3-carbonitrile and o-fluoro-nitrobenzene.…”