Lipophilic 4-imidazoly-1,4-dihydropyridines: synthesis, calcium channel antagonist activity and protection against pentylenetetrazole-induced seizure.
A group of alkyl, cycloalkyl and aryl ester analogs of nifedipine, in which the o-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle, and the activity of 5a-d, 8b and 8f against pentylenetetrazole (PTZ)-induced seizure was assessed. The results for symmetrical esters showed that lengthening of the methylene chain in C3 and C5 ester substituents increased activity. When increasing of the length is accompanied by increasing the hindrance, the activity decreased. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that increasing the length of the methylene chain was accompanied by a decrease in their activity. The results demonstrate that 8a was more active, and 5c and 8f were similar in effect to that of the reference drug nifedipine. The time-course of anticonvulsant effect on PTZ-induced seizure threshold of said compounds was assessed and showed that increasing the lipophilicity decreases the time needed for maximum effect. Mice treated with intraperitoneal injection of 25 mg/kg of these derivatives all exhibited increase seizure threshold as compared with control.
Navidpour
Latifeh
L
Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran 14174, Iran.
Shafaroodi
Hamed
H
Miri
Ramin
R
Dehpour
Ahmad Reza
AR
Shafiee
Abbas
A
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D015220:Calcium Channels / Q000502:physiology; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D008055:Lipids / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D007093:Imidazoles; D008055:Lipids; D010433:Pentylenetetrazole