Synthesis, α 1-adrenoceptor antagonist activity, and SAR study of novel arylpiperazine derivatives of phenytoin

Abstract

In the search for new antiarrhythmic agents, some active 2-methoxyphenylpiperazine derivatives of phenytoin were obtained as a chemical modification of compound AZ-99 (3-ethyl-1-[2-hydroxy-3-(4-phenylpiperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenylimidazolidine). These compounds possessed structural properties similar to those of α 1-adrenoceptor antagonists. In the present study, the affinities of the 2-methoxyphenylpiperazine derivatives ( 1a– 3a) for α 1- and α 2-adrenoceptors were evaluated using radioligand ([ 3H]prazosin, [ 3H]clonidine) binding assays. In the next step, a new series of phenylpiperazine derivatives of phenytoin ( 4a– 16a) containing 2-methoxyphenyl-, 2-ethoxyphenyl-, 2-pyridyl- or 2-furoylpiperazine moiety, as well as, various ester or alkyl substituents at 3-position of hydantoin ring were synthesized. The newly synthesized compounds were tested for their affinity to α 1- and α 2-adrenoceptors. They have shown affinities for α 1-adrenoceptors at nanomolar to submicromolar range. Some compounds were moderately selective ligands of α 1-adrenoceptors. Selected compounds ( 3a– 5a, 7a, 13a, 14a) were also evaluated for their α 1-adrenoceptor antagonistic properties in functional bioassays. A SAR study indicated that the most active compounds contain 2-alkoxyphenylpiperazine moieties and methyl or 2-methylpropionate substituent at 3-N position in hydantoin. The exchange of 2-alkoxyphenyl moiety into 2-furoyl or 2-pyridyl group significantly decreased affinities for α 1-adrenoceptors. Molecular modelling results obtained using conformational analysis CONFLEX and PM5 method for geometry optimization, allowed for comparison of the spatial properties of tested compounds with pharmacophore model created by Barbaro et al. for the ideal α 1-adrenoceptor antagonist.