Molecular pharmacology of UK-118, 434-05, a permanently charged amlodipine analog

Abstract

We studied the effects of UK-118, 434-05, a permanently charged form of amlodipine, on recombinant smooth muscle and cardiac L-type calcium channels to determine the distinct modulatory properties of the ionized form of amlodipine. We found that the short distance between the permanent charge group and the active dihydropyridine (DHP) ring of UK-118, 434-05 reduces the potency of this compound as an inhibitor of smooth muscle (α1c–b) L-type channels, and is similar to the effects of other charged DHP derivatives on cardiac (α1c–a) L-type channels. However, we found surprisingly that the tonic block of cardiac (α1c–a) L-type channels was more pronounced than the tonic block of smooth muscle (α1c–b) L-type channels. This result contrasts with the previously reported subunit-specificity of neutral DHP compounds, and suggests that interactions between the amlodipine charge group and site(s) on the L-type channel α1 subunit distinguish the action of charged from neutral DHPs and may contribute to amlodipine's unique pharmacological profile.