title: 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 (alpha(1c-b)) L-type channels, and is similar to the effects of other charged DHP derivatives on cardiac (alpha(1c-a)) L-type channels. 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 compounds, and suggests that interactions between the amlodipine charge group and site(s) on the L-type channel alpha1 subunit distinguish the action of charged from neutral DHPs and may contribute to amlodipine's unique pharmacological profile.
authors.affiliation: Department of Pharmacology, Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: B
authors.initials: B
authors.lastname: Heath
authors.forename: J
authors.initials: J
authors.lastname: Xia
authors.forename: R S
authors.initials: RS
authors.lastname: Kass
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D017311:Amlodipine; C038806:1,4-dihydropyridine