The agonist pharmacophore of the benzodiazepine receptor. Synthesis of a selective anticonvulsant/anxiolytic

Journal of Medicinal Chemistry
1991.0

Abstract

The benzodiazepines exhibit a wide range of pharmacological actions which include anxiolytic, anticonvulsant, sedative/hypnotic, and myorelaxant effects mediated by specific binding sites in the central nervous system.1 The benzodiazepine receptor (BzR) is one constituent of a supramolecular complex which also contains discrete but allosterically coupled recognition sites for GABA and barbiturates. The oligomeric units of this supramolecular complex form a drug and transmitter responsive chloride channel.2-4 The pharmacological properties of BzR ligands appear to be a continuum,4 ranging from a complete mimicry of 1,4-benzodiazepines (such as diazepam, 2) to substances termed inverse agonists that produce actions best described as opposite to the benzodiazepines.5 Despite advances at the molecular level,6,7 the search continues for selective anxiolytics which are devoid of the other effects typical of the 1,4-benzodiazepines.6 Recently, a computer-assisted analysis of the pharmacophore for inverse agonists at the BzR has been carried out,7 which has resulted in the synthesis of the long-lived inverse agonist, 3-ethoxy-β-carboline.8 In order to employ a rational drug design to prepare selective agonists at the BzR,9 a similar approach has been employed with ligands defined as BzR agonists. As a result of these studies we wish to report the synthesis of a new anxiolytic/anticonvulsant, 6-(n-propoxy)-4-(methoxymethyl)-β-carboline-3-carboxylic acid ethyl ester (6-PBC, 1) which is devoid of myorelaxant and ataxic effects.

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