MOLECULAR PHARMACOLOGY OF UK-118,434-05, A PERMANENTLY CHARGED AMLODIPINE ANALOG

We studied the effects of UK-118, 434-05, a permanently charged form o f amlodipine, on recombinant smooth muscle and cardiac L-type calcium channels to determine the distinct modulatory properties of the ionize d form of amlodipine. We found that the short distance between the per manent charge group and the active dihydropyridine (DHP) ring of UK-11 8, 434-05 reduces the potency of this compound as an inhibitor of smoo th muscle (alpha(1c-b)) L-type channels, and is similar to the effects of other charged DHP derivatives on cardiac (alpha(1c-a)) L-type chan nels. However, we found surprisingly that the tonic block of cardiac ( alpha(1c-a)) L-type channels was more pronounced than the tonic block of smooth muscle (alpha(1c-b)) L-type channels. This result contrasts with the previously reported subunit-specificity of neutral DHP compou nds, and suggests that interactions between the amlodipine charge grou p and site(s) on the L-type channel alpha(1) subunit distinguish the a ction of charged from neutral DHPs and may contribute to amlodipine's unique pharmacological profile. (C) 1997 Elsevier Science Ireland Ltd.