Synthesis and antinociceptive activity of 4-pyridyl and -dihydropyridyl analogues of meperidine and ketobemidone.
The synthesis and antinociceptive activity of 4-pyridylpiperdines (7 and 10) in which the phenyl group pf meperidine (1) or ketobemidone (3) is replaced by 2'-, 3'- or 4'-pyridyl is described. All were active in a rat writhing test, and the results showed that the point of attachment of the pyridyl ring to the 4-position was an important determinant of the activity; the relative potency order was 3'-pyridyl greater than 4'-pyridyl greater than 2'-pyridyl in each of the two series. The most potent compound (half the potency of meperidine) was 4-ethoxycarbonyl-4-(3'-pyridyl)-l-methylpiperidine (7b). This compound, and the corresponding 4'-isomer (7c), were further elaborated to provide 1'-phenyl, 1',6'-dihydropyridine (11), and 1'-phenyl, methyl or n-butyl. 1',2'-dihydropyridine (12) analogues containing an acyl function on the ring nitrogen. The most active compound in this series was 4-[4'-(1'-phenoxycarbonyl-2'-n-butyl-l',2'-dihydropyridyl)]- 4- ethoxycarbonyl-l-methylpiperdine (12k). Though less potent than the parent pyridyl compound (7c), it induced 70% inhibition in the writhing test at a dose of 8 mg/kg sc. [The ED50 for meperidine was 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; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008614:Meperidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D000700:Analgesics; D000701:Analgesics, Opioid; D008614:Meperidine; C012394:ketobemidone