New 1,4-dihydropyridines endowed with NO-donor and calcium channel agonist properties.
A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved to be potent calcium channel agonists. All the racemic mixtures, with the only exception of the carbamoyl derivatives 9, 12 endowed with scanty solubility, were separated by chiral chromatography into the corresponding enantiomers; the (+) enantiomers were found to be potent agonists while the (-) ones were feeble antagonists. The racemic mixtures were also assessed for their positive inotropic activity on electrically stimulated rat papillary muscle and for their ability to increase Ca(2+) entry into the vascular smooth muscle of rat aorta strips. The cyanofuroxan 8 proved to be an interesting product with dual Ca(2+)-dependent positive inotropic and NO-dependent vasodilating activity.
Visentin
Sonja
S
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Pietro Giuria 9, I-10125 Torino, Italy.
Rolando
Barbara
B
Di Stilo
Antonella
A
Fruttero
Roberta
R
Novara
Monica
M
Carbone
Emilio
E
Roussel
Christian
C
Vanthuyne
Nicolas
N
Gasco
Alberto
A
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents