The calcium channel antagonists, including verapamil, nifedipine, and diltiazem, are a major class of drugs active in cardiovascular medicine."' Since their discovery (reviewed by Flecken~tein~) a number of questions have been posed that have served to define the sites and mechanisms of action of these agents. These questions may be summarized as fol10ws:~ (1) Are the specific sites of action discrete or multiple? What are the structure-activity relationships? (2) Are mobilization and currents involved in a relationship to Ca"? (3) Is the specificity of action in specific tissues or organs? What is the basis for the specificity? (4) How are membranes and sidedness involved in multiple sites of action? (5) Are the mechanisms single or multiple? There is now quite general agreement that, consistent with their chemical and pharmacologic heterogeneity, verapamil, nifedipine, and diltiazem (FIG. l), as representatives of the phenylalkylamine, 1,4-dihydropyridine, and benzothiazepine chemical classes, respectively, interact at three distinct sites that are located on a major protein, the nonglycosylated alpha, subunit of the voltage-gated L class of These sites are linked allosterically one to the other and to the functional machinery of the channel (FIG. 1). The 1,4-dihydropyridine structure, including Bay K 8644 and PN 202 791, and possibly the phenylalkylamine and benzothiazepine structures also, expresses potent activator properties (FIG. 1).* Furthermore, within the 1,4-dihydropyridine structure potent activator and antagonist properties may exist within the enantiomers of a single structure.' Expression of the alpha, protein shows that it possesses the major properties of the Ca" channellox1' and that it exists in several subclasses.'2 Although these agents all interact at a single category of Caz+ channel and although these channels are widespread in excitable tissues, there is considerable selectivity of drug action. The actions of current therapeutically available agents dominate in the cardiovascular system, and they exhibit also a significant range of cardiac:vascular selectivity (FIG. 1). Furthermore, the selectivity of the agents may be distinguished not only between groups, but also within groups. Thus, the 1,4- dihydropyridine structure embraces a range of activity from the normal vascular selective agents to more recently described cardiac selective agents
Triggle, D.J., Hawthorn, M., Gopalakrishnan, M., Minarini, A., Avery, S., Rutledge, A., et al. (1991). Synthetic organic ligands active at voltage-gated calcium channels. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 635(1), 123-138 [10.1111/j.1749-6632.1991.tb36487.x].
Synthetic organic ligands active at voltage-gated calcium channels
Minarini, AWriting – Original Draft Preparation
;
1991
Abstract
The calcium channel antagonists, including verapamil, nifedipine, and diltiazem, are a major class of drugs active in cardiovascular medicine."' Since their discovery (reviewed by Flecken~tein~) a number of questions have been posed that have served to define the sites and mechanisms of action of these agents. These questions may be summarized as fol10ws:~ (1) Are the specific sites of action discrete or multiple? What are the structure-activity relationships? (2) Are mobilization and currents involved in a relationship to Ca"? (3) Is the specificity of action in specific tissues or organs? What is the basis for the specificity? (4) How are membranes and sidedness involved in multiple sites of action? (5) Are the mechanisms single or multiple? There is now quite general agreement that, consistent with their chemical and pharmacologic heterogeneity, verapamil, nifedipine, and diltiazem (FIG. l), as representatives of the phenylalkylamine, 1,4-dihydropyridine, and benzothiazepine chemical classes, respectively, interact at three distinct sites that are located on a major protein, the nonglycosylated alpha, subunit of the voltage-gated L class of These sites are linked allosterically one to the other and to the functional machinery of the channel (FIG. 1). The 1,4-dihydropyridine structure, including Bay K 8644 and PN 202 791, and possibly the phenylalkylamine and benzothiazepine structures also, expresses potent activator properties (FIG. 1).* Furthermore, within the 1,4-dihydropyridine structure potent activator and antagonist properties may exist within the enantiomers of a single structure.' Expression of the alpha, protein shows that it possesses the major properties of the Ca" channellox1' and that it exists in several subclasses.'2 Although these agents all interact at a single category of Caz+ channel and although these channels are widespread in excitable tissues, there is considerable selectivity of drug action. The actions of current therapeutically available agents dominate in the cardiovascular system, and they exhibit also a significant range of cardiac:vascular selectivity (FIG. 1). Furthermore, the selectivity of the agents may be distinguished not only between groups, but also within groups. Thus, the 1,4- dihydropyridine structure embraces a range of activity from the normal vascular selective agents to more recently described cardiac selective agentsI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
