title: Permanently charged chiral 1,4-dihydropyridines: molecular probes of L-type calcium channels. Synthesis and pharmacological characterization of methyl(omega-trimethylalkylammonium) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate iodide, calcium channel antagonists.
abstract: We report the synthesis of the single enantiomers of permanently charged dihydropyridine derivatives (DHPs with alkyl linker lengths of two and eight carbon atoms) and their activities on cardiac and neuronal L-type calcium channels. Permanently charged chiral 1,4-dihydropyridines and methyl (omega)-trimethylalkylammonium) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate iodides were synthesized in high optical purities from (R)-(-) and (S)-(+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-+ ++pyridinecarboxylic acid, obtained by resolution of racemic 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-pyridi necarboxylic acid. Competition binding experiments with radioligand [3H]-(+)-PN200-110 and the block of whole cell barium currents through L-type calcium channels in GH4C1 cells show that the compounds with the eight-carbon alkyl linker optimally block the L-type Ca2+ channels, and that the S-enantiomer is more potent than the R-enantiomer.
authors.affiliation: Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo, 14260, USA.
authors.forename: R
authors.initials: R
authors.lastname: Peri
authors.forename: S
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: A
authors.initials: A
authors.lastname: Rutledge
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: D J
authors.initials: DJ
authors.lastname: Triggle
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009206:Myocardium / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines