Synthesis, α1-adrenoceptor antagonist activity, and SAR study of novel arylpiperazine derivatives of phenytoin Original Research Article

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 α1-adrenoceptor antagonists. In the present study, the affinities of the 2-methoxyphenylpiperazine derivatives (1a–3a) for α1- and α2-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 α1- and α2-adrenoceptors. They have shown affinities for α1-adrenoceptors at nanomolar to submicromolar range. Some compounds were moderately selective ligands of α1-adrenoceptors. Selected compounds (3a–5a, 7a, 13a, 14a) were also evaluated for their α1-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 α1-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 α1-adrenoceptor antagonist.