Synthesis and structure-activity relationships of new arylpiperazines: para substitution with electron-withdrawing groups decrease binding to 5-HT(1A) and D(2A) receptors.

Compounds in which N-phenylpiperazines were linked by a propyloxy chain to position 6 or 7 of a coumarin ring were designed and synthesised, and their affinities for 5-HT(1A) and D(2A) receptors were determined by radioligand binding assays. The influence of para substitution in the phenyl ring, substitution at position 4 of the coumarin system, and the coumarin position at which the piperazinylalkyl chain is linked was explored. Electron-withdrawing phenyl ring substituents para to the piperazine strongly reduced activity at both receptors. Binding at 5HT(1A) was influenced by the bulk of substituents at position 4 of the coumarin system, and binding at D(2A) by their electronic properties. Neither binding affinity was significantly affected by whether the piperazinylalkyl chain was inserted at position 6 or 7 of the coumarin system.