Assessment of the in vivo and in vitro opioid activity of bridged hexahydroaporphine and isoquinoline molecules.
Four novel racemic bridged hexahydroaporphine (1 and 2) and isoquinoline (3 and 4) analogues have been synthesized in an attempt to generate bicyclic derivatives of the morphinan ring system. The opioid activity of these analogues has been assessed through membrane-binding studies, in vitro studies in isolated guinea pig ileum and mouse vas deferens, and in vivo studies utilizing the mouse hot plate technique. The bridged isoquinoline precursor molecules were inactive as antinociceptives. Both the racemic phenolic hexahydroaporphine 1 and its 10-methoxy congener 2 demonstrated dose-dependent, albeit weak, antinociceptive activity when administered icv, but they induced lethal convulsions when given subcutaneously. The antinociception elicited by 1 appeared to show very weak opioid character while that caused by 2 was totally nonopioid.
Roche
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VF
Department of Pharmaceutical Sciences, School of Pharmacy and Allied Health Professions, Creighton University, Omaha, Nebraska 68178.
Roche
E B
EB
Lemcke
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PK
Wire
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WS
Burks
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TF
D000698:Analgesia; D000818:Animals; D001060:Aporphines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009119:Muscle Contraction; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D001060:Aporphines; D001952:Bridged-Ring Compounds; D007546:Isoquinolines; D011957:Receptors, Opioid