Synthesis and antinociceptive activity of 2- and 3-methyl derivatives of 4-(pyridyl) isosteres of meperidine.
The respective cis- and trans-[3-Me,4-(pyridyl)] diastereoisomers of 4-(2-pyridyl)- (8a and 8b), 4-(3-pyridyl)- (8d and 8e) and 4-(4-pyridyl)-1,3-dimethyl-4-ethoxycarbonylpiperidines (8h and 8i) were synthesized for evaluation as 3-methyl substituted isosteres of meperidine. Alkylation of ethyl 2-, 3- or 4-pyridylacetate (7) with N-(2-chloroethyl)-N-(2-chloropropyl)methylamine (6) afforded the respective 3-methyl substituted compounds 8a and 8b, 8d and 8e or 8h and 8i, together with the corresponding 2-methyl substituted compounds 8c (only the trans-isomer was obtained), 8f and 8g, or 8j and 8k. Antinociceptive test results, acquired using the 4% sodium chloride assay in rats, indicated that a cis-3-methyl substituent usually enhanced antinociceptive potency slightly, whereas a trans-3-methyl substituent lowered activity 3-4 fold relative to the parent 3-unsubstituted compounds 3b-d, at a dose of 2 mg/kg sc. A trans-2-methyl substituent (8g and 8k), like a cis-methyl substituent (8a, 8d and 8h), also maintained or provided a small increase in antinociceptive activity. Trans-1,2-Dimethyl-4-ethoxycarbonyl-4-(3-pyridyl)piperidine (8g) and cis-1,3-dimethyl-4-ethoxycarbonyl-4-(4-pyridyl)piperidine (8h) were the most active antinociceptives producing a 66% inhibition of writhing at a dose of 2 mg/kg sc, relative to the reference drug meperidine (ED50 = 0.6 mg/kg sc).
Buolamwini
J K
JK
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Knaus
E E
EE
D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D008614:Meperidine / Q000031:analogs & derivatives*; D009619:Nociceptors / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D006571:Heterocyclic Compounds; D010880:Piperidines; D008614:Meperidine