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.

Quercetin as a novel activator of L‐type Ca2+channels in rat tail artery smooth muscle cells

“…Naturally occurring molecules such as heparin (Knaus et al ., 1990) and certain animal toxins (Hamilton & Perez, 1987), have been shown to stimulate L‐type Ca 2+ channels in various mammalian tissues. Among the synthetic Ca 2+ channel ligands, some dihydropyridine derivatives such as Bay K 8644 (Hess et al ., 1984), CGP 28392 (Kokubun & Reuter, 1984), RS 30026 (Patmore et al ., 1990) and (+) 1,4‐dihydro‐2,6‐dimethyl‐5‐nitro‐4‐(benzofuran‐5‐yl)pyridine‐3‐carboxylate (Visentin et al ., 1999) as well as FPL 64176, a benzoylpyrrole compound (Rampe & Lacerda, 1991), have been shown to possess predominantly agonist‐like activity.…”

G-protein- and cAMP-dependent L-channel gating modulation: a manyfold system to control calcium entry in neurosecretory cells

“…This may suggest the presence of a short lasting voltage-dependent facilitation that does not outlast channel closing [68,70,85], but we attributed part of the facilitation to a direct action of the DHP on L-channel gating. Indeed, in RINm5F cells containing large percentages of L-channels, Bay K 8644 and other DHP agonists are able to induce a variable delay of L-channel activation and exhibit voltage-dependent facilitation with double-pulse stimulation [49,98].…”

Synthesis of novel unsymmetrically substituted 1,4-dihydropyridines and separation of the enantiomers of racemic 1,4-dihydropyridine containing isothioureido group

“…The 1,4-dihydropyridine Ca 2+ channel blockers are clinically significant antihypertensive drugs [1][2][3] and have been immensely valuable as molecular tools with which probe structural and functional aspects of Ca 2+ channel function. 4,5 Most of the 1,4-dihydropyridines were prepared via the Hantzsch procedure.…”