title: Comparison of binding affinities and negative inotropic potencies of the 1,4-dihydropyridine calcium channel blockers in rabbit myocardium.
abstract: The binding and pharmacologic response of a series of 1,4-dihydropyridine analogs were examined in rabbit myocardium. [3H]Nitrendipine was used to label specific binding sites in myocardial membrane particulates and displacement experiments were carried out with the unlabeled analogs to determine their IC50 values. Binding of [3H]nitrendipine could be characterized by a Kd of 0.15 +/- 0.06 nM and a maximum number of binding sites of 247 +/- 150 fmol/mg of protein. Saturation binding experiments performed with higher concentrations of [3H]nitrendipine did not reveal the presence of a lower affinity site. Binding IC50 values of 12 unlabeled 1,4-dihydropyridine analogs ranged from 4.3 X 10(-10) M to 1.32 X 10(-6) M. The negative inotropic effect of the same compounds was studied in vitro in isolated papillary muscles and the IC50 values for inhibition of contraction determined. There was a statistically significant correlation between the IC50 values for binding and response (r = 0.79, P less than .005; rs = 0.78, P less than .005). Consistent with previous studies with several of these compounds, the response IC50 value for each compound was greater than the binding IC50 value. For most of the compounds, this difference was from one to two orders of magnitude. For three compounds, nitrendipine, nimodipine and nicardipine, this difference reached three orders of magnitude. These three dihydropyridine analogs share structural features that may determine their low myocardial potency and, at the same time, their high vascular smooth muscle potency. Elucidation of these structural features may be useful in determining which analogs will have the highest vascular smooth muscle selectivity.
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of California, San Francisco.
authors.forename: R A
authors.initials: RA
authors.lastname: Boyd
authors.forename: J C
authors.initials: JC
authors.lastname: Giacomini
authors.forename: F M
authors.initials: FM
authors.lastname: Wong
authors.forename: W L
authors.initials: WL
authors.lastname: Nelson
authors.forename: K M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D015220:Calcium Channels; D004095:Dihydropyridines / Q000378:metabolism* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D011978:Receptors, Nicotinic