Pharmacological effects of 1,2,3,5,6,10b-hexahydropyrido[2,3g]indolizine, a bridged-nicotine analog.
The racemate of a bridged-nicotine (BN) analog was synthesized and resolved into its enantiomers for pharmacological comparisons to (+)- and (-)-nicotine. The EC50 values for (-)- and (+)-nicotine and (-)- and (+)-BN were 4, 170, 53 and 400 microM, respectively, for producing contractions of guinea-pig ilea. (-)-Nicotine was an effective antinociceptive agent in the mouse tail-flick procedure at i.v. doses of 0.1-0.3 mg/kg, whereas the isomers of BN failed to alter tail-flick response in doses up to 5 mg/kg. (-)-Nicotine (0.01-0.3 mg/kg, i.v.) increased blood pressure and decreased heart rate in anesthetized rats. Neither (+)- nor (-)-BN altered blood pressure and heart rate in rats in this dosage range. At doses of 3-100 mg/kg, (+)-BN produced an increase in blood pressure without changing heart rate, while (-)-BN decreased both blood pressure and heart rate. Bridging the pyrrolidine and pyridine rings decreased biologic activity and did not result in stereoselectivity greater than that observed with (+)- and (-)-nicotine. It appears that there may be subpopulations of nicotine receptors to which the isomers of BN do not interact.
D000700:Analgesics; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000502:physiology; D007212:Indolizines / Q000494:pharmacology*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D000700:Analgesics; D007212:Indolizines; C047736:1,2,3,4,5,10b-hexahydropyrido(2,3-g)indolizine; D008464:Mecamylamine; D009538:Nicotine