title: Synthesis and voltage-clamp studies of methyl 1,4-dihydro-2, 6-dimethyl-5-nitro-4-(benzofurazanyl)pyridine-3-carboxylate racemates and enantiomers and of their benzofuroxanyl analogues.
abstract: Racemic methyl 1,4-dihydro-2, 6-dimethyl-5-nitro-4-(benzofurazanyl)pyridine-3-carboxylates (+/-)-10 and (+/-)-11 and their benzofuroxanyl analogues (+/-)-12 and (+/-)-13 were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with methyl 3-aminocrotonate and the appropriate aldehydes. The racemic mixtures were resolved into the corresponding enantiomers. Whole-cell voltage-clamp studies on L-type Ca2+ channels expressed in a rat insulinoma cell line (RINm5F) showed that all the dextrorotatory antipodes were effective agonists of L-type Ca2+ currents, while the levorotatory ones were weak Ca2+ entry blockers. The (+)-enantiomer of benzofurazan-5'-yl derivative 11 demonstrated unusual activity in that, in addition to producing a potentiation of L-type currents, it interfered with the voltage-dependent gating of L-type channels by producing a net delay of their activation at low voltages. This compound represents an interesting tool to probe L-type Ca2+ channel structure and function.
authors.affiliation: Department of Scienza e Tecnologia del Farmaco, Facoltà di Farmacia, Università degli Studi di Torino, via P. Giuria 9, 10125 Torino, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Visentin
authors.forename: P
authors.initials: P
authors.lastname: Amiel
authors.forename: R
authors.initials: R
authors.lastname: Fruttero
authors.forename: D
authors.initials: D
authors.lastname: Boschi
authors.forename: C
authors.initials: C
authors.lastname: Roussel
authors.forename: L
authors.initials: L
authors.lastname: Giusta
authors.forename: E
authors.initials: E
authors.lastname: Carbone
authors.forename: A
authors.initials: A
authors.lastname: Gasco
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D020746:Calcium Channels, L-Type; D015640:Ion Channel Gating; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
chemical_list: D001583:Benzoxazoles; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D011725:Pyridines