Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor

Abstract

Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxylate], Bay O 8495 [methyl l,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5-carboxylate], and Bay O 9507 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(4-nitrophenyl)-pyridine-5-carboxytate] were determined. The conformations of the 1,4-DHP rings of these activator analogues of Bay K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate] do not suggest that their activator properties are as strongly correlated with the degree of 1,4-DHP ring flattening as was indicated for members of the corresponding antagonist series. The solid state hydrogen bonding of the N(1)-H groups of the activators is not, unlike that of their antagonist counterparts, to acceptors that are directly in line with the donor. Rather, acceptor groups are positioned within _+ 60 degrees of the N(1)-H bond in the vertical plane of the 1,4-DHP ring. Previously determined structure-activity relationships have indicated the importance of this N(1)-H group to the activity of the 1,4-DHP antagonists. Based on these observations, a model is advanced to describe the 1,4-DHP binding site of the voltage-gated Ca 2÷ channel and its ability to accommodate both antagonist and activator ligands.

Theoretical studies applicable to the design of novel anticonvulsants: an AM1 molecular orbital structure–activity study of dihydropyridine calcium channel antagonists

“…These data may also support the recent binding model by Langs et al (29,31), which postulates that the active conformer of a DHP has sp/sp ester orientation. Provided binding transition state energies are not large, the populations of various conformers may influence their binding and thus pharmacologic activity.…”

Synthesis and calcium channel modulation effects of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-phenylpyridine-5-carboxylates possessingortho-,meta-, andpara-CH2S(O)nMe and -S(O)nMe (n = 0-2) phenyl substituents

“…In this respect, affinity for different gating-states of the CC may vary depending on structural and conformational features that are relevant to binding to the α 1 -subunit of the L-type CC [Langs et al, 1991].…”

Design and syntheses of 4-[3-(1-methoxycarbonyl-1,6-dihydropyridyl)]- and 4-[3-(1-methoxycarbonyl-4-substituted-1,4-dihydropyridyl)]- derivatives of alkyl 1,4-dihydro-2,6-dimethyl-3-nitro-5-pyridine-carboxylates with calcium channel modulating activities

“…[1][2][3] Accordingly, the prototype 1,4-DHP CC agonist (S)-(+)-Bay K 8644 1 simultaneously promotes calcium entry into vascular smooth muscle, inducing vasconstriction, that prevents its clinical use for the treatment of congestive heart failure (CHF). [4][5] Recently, we discovered a novel third generation class of isomeric isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridyl)-5-pyridinecarboxylates 2a-c with different CC modulation activities.…”