Soft drug derivatives related to perhexiline. Part I: In vitro studies.
A series of cyclohexylaralkylamines derived from perhexiline was synthesized according to the "soft drug" concept. An amide function was introduced as a labile centre to give non-toxic moieties in vivo after the "soft drugs" had attained their therapeutic aims. Compounds were evaluated for their alpha-adrenolytic, calcium antagonist and vasodilator activities in vitro. Some of them, 2, 3, 7 and 15 on rat aorta had alpha-adrenolytic effects comparable to that of perhexiline. Most of them were about 10 times more active calcium antagonists on depolarized pig coronary artery than perhexiline. All derivatives produced concentration-related coronary dilation in the perfused guinea pig heart. Compound 2 was equipotent to perhexiline. The decrease in coronary resistance might, at least partly, be attributable to the alpha-blocking properties of the molecules. In conclusion, the introduction of an amide function into the perhexiline skeleton does not markedly alter the in vitro pharmacological properties.
Decker
N
N
Institut de Pharmacologie, Faculté de Médecine, Strasbourg, France.
Grima
M
M
Velly
J
J
Marciniak
G
G
Leclerc
G
G
Schwartz
J
J
D000317:Adrenergic alpha-Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers; D003326:Coronary Circulation / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D010477:Perfusion; D010480:Perhexiline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D013552:Swine; D014665:Vasodilator Agents
D000317:Adrenergic alpha-Antagonists; D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; D010480:Perhexiline