Structure-activity relationship of quaternary ion antagonism of levcromakalim-induced relaxation in pig coronary artery.

The aim of this study was to investigate the interaction between the K+ channel opener levcromakalim and several quaternary ions. Cumulative vasorelaxant-response curves to levcromakalim were constructed in the absence and in the presence of the quaternary ions, in the pig coronary artery. The most potent compounds (based on 'apparent pKB' values) were: propyltriphenylphosphonium (7.33), butyltriphenylphosphonium (7.04), tetraphenylarsonium (6.86), tetraphenylphosphonium (6.81), ethyltriphenylphosphonium (6.70), and hexyltriphenylphosphonium (6.63). Tetrabutylphosphonium (6.06), tetrabutylammonium (5.12), methyltriphenylphosphonium (5.25), clofilium (5.66) and guanethidine (5.61) were significantly less potent. Tetrapropylammonium, tetrapentyltin and tetraphenylboron were inactive at the maximum concentrations used (30 microM). Tetraphenylboron (10-100 microM) fully reversed tetraphenylphosphonium, tetraphenylarsonium (both at 3 microM), tetrabutylammonium (30 microM) and clofilium (10 microM) and partially reversed guanethidine (10 microM) antagonism of levcromakalim responses indicating a similarity in the mechanism of action of these chemically distinct compounds. The results show that quaternary ions similar in structure to tetraphenylphosphonium, i.e., containing phosphonium ion centre and phenyl side chains, are the most potent antagonists of levcromakalim, in pig coronary artery. It is also apparent that marked changes can be made in the substitution on the phosphonium ion (ethyl to hexyl) with little or no effect on their potency.