New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.
A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.
Marciniak
G
G
Institut de Pharmacologie (UA 589 CNRS), Faculté de Médecine, Strasbourg, France.
Delgado
A
A
Leclerc
G
G
Velly
J
J
Decker
N
N
Schwartz
J
J
D000818:Animals; D001011:Aorta / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D002122:Calcium Chloride / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003331:Coronary Vessels / Q000502:physiology; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009568:Nitrendipine / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D013552:Swine; D014649:Vas Deferens / Q000378:metabolism; D015016:Yohimbine / Q000378:metabolism
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D009568:Nitrendipine; D002122:Calcium Chloride; D011224:Prazosin