Abstract: A series of phenylpiperazine derivatives of phenytoin was evaluated for their affinity at α1-adrenoceptor subtypes in functional bioassays (rat tail artery: α1A and/or α1B; guinea pig spleen: α1B; rat aorta: α1D). The most potent compounds at α1A-, α1B- and α1D-adrenoceptors, 11, 18 and 8, showed affinities in the submicromolar range. The role of a hydrogen bond donor group for affinity and selectivity at α1B-adrenoceptors, postulated by Bremner’s pharmacophore model, was confirmed by functional and molecular modelling studies. [Copyright &y& Elsevier]