Synthesis of 7-arylmorphinans. Probing the "address" requirements for selectivity at opioid delta receptors.
Through arylation of 6-keto opiates with diaryliodonium iodide, a series of 7-aryl opiates (3-8) have been prepared in an effort to investigate the effect of conformational mobility of the delta "address" moiety on opioid agonist and antagonist potencies. Evaluation of the ligands in the mouse vas deferens and guinea pig ileum preparations revealed that they were less potent and less selective than the conformationally constrained ligands, naltrindole (1, NTI) and 7-(spiroindanyl)oxymorphone (2, SIOM), at delta opioid receptors. It is concluded that the coplanarity of the address moiety with the C ring of the morphinan structure enhances delta antagonist potency and selectivity.
Gao
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Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 308 Harvard Street S.E., Minneapolis, Minnesota 55455, USA.
Larson
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Portoghese
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D000818:Animals; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010111:Oxymorphone / Q000031:analogs & derivatives / Q000494:pharmacology; D010147:Pain Measurement; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D008024:Ligands; D009019:Morphinans; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D013141:Spiro Compounds; C082822:7-spiroindanyloxymorphone; D009271:Naltrexone; D010111:Oxymorphone; C055382:naltrindole