In-vivo metabolism of 4-substituted arylpiperazines to pharmacologically active 1-arylpiperazines

Abstract

A common metabolic process of 4-substituted arylpiperazine pharmacological agents is cleavage of the side-chain to yield 1-arylpiperazines. These metabolites are a well-known class of centrally active compounds and their formation may therefore be a pharmacologically significant pathway, at least in certain species, for derivates that undergo extensive cleavage of the arylpiperazine side-chain. Of pharmacological relevance is the observation that they may have a spectrum of pharmacological actions different from the parent compound(s). As illustrated by the anxiolytic agent buspirone, its derivates gepirone and isapirone and their common metabolite 1-(2-pyrimidinyl)-piperazine (PmP), parents drug(s) and metabolite may have quite different mechanism of action. In other cases, the 1-arylpiperazine metabolite and its parent drug(s) may act antagonistically (i.e. 1-(m-chlorophenyl)-piperazine, mCIPP, and its parent drugs trazodone and etoperidone). The kinetic properties of 1-arylpiperazine metabolites may differ from those of the parent compound, particularly in relation to the extent to which they enter the brain, the site of action of most of these compounds. The examples given although limited, provide evidence that kinetics and pharmacological studies on 1-arylpiperazine metabolites are important in seeking to understand the mechanism of action of the 4-substituted derivatives and in extrapolating pharmacological finding from animals to man.