1,4‐Dihydropyridine Ca²⁺channel antagonists and activators: A comparison of binding characteristics with pharmacology

Abstract

This comparison of the binding characteristics and pharmacology of 1,4-dihydropyridines indicates that the high-affinity binding sites studied in cardiac and smooth muscle cells represent a major site of action of these drugs, and that this site is the Ca2+ channel or a closely related protein. Electrophysiological studies suggest that the effects of both Ca2+ channel inhibitors and activators are voltage dependent. The apparent lack of agreement between the equilibrium dissociation constants for [3H]1 ,4-dihydropyridines and their potency in cardiac muscle may be due to conformational modifications that occur in the 1,4-dihydropyridine binding site as a result of voltage or other changes during membrane isolation. The selective effect of 1 ,4-dihydropyridines for vascular smooth muscle relative to cardiac muscle may be explained, in part, by differences in membrane potentials and Ca2+ channel regulatory mechanisms and, in part, by differences in receptor structure. 1,4-Dihydropyridine antagonists and activators appear to bind to a common site that is not the same as the binding site for nondihydropyridine Ca2+ channel antagonists.

Direct activation of Ca2+ channels by palmitoyl carnitine, a putative endogenous ligand

“…Under constant depolarizing conditions, the calcium-antagonistic effects ofother dihydropyridines such as nifedipine are competitively antagonized by Bay K 8644 (Su et al, 1984;Spedding, 1985a). The effects of the class II antagonists such as verapamil and diltiazem are reversed non-competitively (Schramm & Towart, 1984;Su et al, 1984;Spedding, 1985a), which is consistent with the allosteric linkage between the binding sites for these drugs in the Ca2" channel (Janis & Triggle, 1984;Glossmann et al, 1986). In complete contrast, Bay K 8644 does not reverse the inhibitory effects of class III calcium-antagonists such as cinnarizine or flunarizine (Spedding & Berg, 1984); this discrepancy is consequent upon these agents having a molecular site of action which may either be in VOCs (Godfraind & Miller, 1983), trapping the channels in a state which has low affinity for dihydropyridines, or be at other sites (Spedding, 1985b;Grima et al, 1986).…”

Inhibition of myocardial Ca2+ channels by three dihydropyridines with different structural features: potential‐dependent blockade by Ro 18–3981

“…Dihydropyridine (DHP) Ca2" channel blockers such as nifedipine and nitrendipine are presumed to inhibit the myocardial slow inward Ca2" current (1Ca) by interacting with receptors located on the Ca2" channel (Janis & Triggle, 1984). Extensive investigations have documented the existence of high-affinity DHP binding sites in cardiac membranes (Bellemann et al, 1981;Holck et al, 1982; Triggle & Janis, 1984a).…”

“…Extensive investigations have documented the existence of high-affinity DHP binding sites in cardiac membranes (Bellemann et al, 1981;Holck et al, 1982; Triggle & Janis, 1984a). However, when comparing results of pharmacological and electrophysiological studies (Lee & Tsien, 1983; Janis & Triggle, 1984) with those from binding studies (Holck et al, 1982;1984), a large discrepancy (> 10 fold) is encountered in the concentrations of DHPs required to suppress myocardial ICa and to inhibit [3H1-nitrendipine binding. Recent investigations suggest that the Ca2" channel blocking potencies of DHPs such as nitrendipine (Bean, 1984;Reuter et al, 1985) or 'Author for correspondence. nisoldipine (Sanguinetti & Kass, 1984) Hof, 1985).…”

3,5-Dimethoxycarbonyl-2,6-dimethyl-4-(2-nitrosophenyl)pyridine and Dichlorobis[3,5-dimethoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)pyridine]copper(II)

“…The existence of these decomposition products has led to concern about shelf-life, packaging and potency (Ntinez-Vergara, Sunkel & Squella, 1994;Sadana & Ghogare, 1991;Hayase, Itagaki, Ogawa, Akutsu, Inagaki & Abiko, 1994 Calcium antagonistic activity of the 1,4-dihydropyridine family is influenced by (a) the presence of the 1,4-dihydropyridine moiety, (b) alkyl groups (preferably methyl) substituted at the 2 and 6 positions, (c) ester groups at the 3 and 5 positions, (d) an aryl (phenyl) substituent at position 4 and (e) N--H at position 1. Oxidation of the 1,4-hydropyridine ring to pyridine is reported to diminish activity significantly (Triggle, Langs & Janis, 1989;Morad, Goldmann & Trentham, 1983;Loev, Goodman, Snader, Tedeschi & Macko, 1974;Janis, Silver & Triggle, 1987).…”