Molecular Pharmacology of the Calcium Channel

Analysis of the Dihydropyridine Receptor Site ofl-type Calcium Channels by Alanine-scanning Mutagenesis

“…Allosteric Interactions among Dihydropyridines, Phenylalkylamines, and Benz(othi)azepines-Ligand binding studies indicate that the phenylalkylamines, benz(othi)azepines, and DHPs bind to three separate receptor sites that interact allosterically (4,5). This requires that all three classes of drugs be able to occupy their receptor sites simultaneously.…”

“…L-type Ca 2ϩ channels are the molecular targets for the dihydropyridine, phenylalkylamine, and benz(othi)azepine classes of calcium channel blockers that are widely used in the therapy of cardiovascular diseases. These drugs are thought to bind to three separate but allosterically coupled receptor sites on L-type Ca 2ϩ channels (4,5). The L-type Ca 2ϩ channels consist of the pore-forming ␣ 1 subunits of 190 -250 kDa in association with disulfide-linked ␣ 2 ␦ subunits of approximately 140 kDa, intracellular ␤ subunits of 55-72 kDa, and, for the skeletal muscle L-type channel, an additional transmembrane ␥ subunit of 33 kDa (for review see Ref.…”

Iminium ion-mediated cyclizations of 4-aryl-1,4-dihydropyridines. Alternate cyclization pathways

“…This was purified by careful flash chromatography on silica gel (230-400 mesh), eluting with hexane-ether (1:2) to afford 1.48 g (74%) of a mixture of 14 and 15, eluting first with an Ri0.5, followed by 0.24 g (12% of 11, Rf0. 4 2,4a,9,9a-tetrahydro-6-methoxy-1,3,9-trirnethyl-l H-indeno[2, I -c]pyridine-4-9a(a)-dicarboxylate (1 6) To 5 mL glacial acetic acid was added 0.06g (1.6 mmol) sodium borohydride at room temperature and, after the initial vigorous gas evolution, this suspension was stirred for 15min. Then 0.10g (0.28 mmol) of a mixture of 14/15 (1: 1.25) was added in one portion and the resulting yellow solution was stirred at room temperature overnight. '…”

“…Among these, the 4-aryl-1,4-dihydropyridines, as characterized by nifedipine (I), have proven to be the most potent. Development and further refinement of biologically active dihydropyridines have involved molecular classification according to drug receptor site and specific channel gating characteristics (4,5). Pharmacologic progress in this area has hinged on the evolution of synthetic strategies that would provide molecules of appropriate topology.…”

Molecular Determinants of High Affinity Phenylalkylamine Block of l-type Calcium Channels in Transmembrane Segment IIIS6 and the Pore Region of the α1Subunit

“…Three major classes of L-type Ca 2ϩ channel blockers are currently in clinical use, dihydropyridines, benz(othi)-azepines, and phenylalkylamines. Drugs from all three classes bind to the pore-forming ␣ 1 subunit of L-type Ca 2ϩ channels in a manner that suggests that their binding sites are closely linked (5,6). Recently, much progress has been made toward the characterization of Ca 2ϩ antagonist receptor sites at the molecular level (for review see Ref.…”