7-Arylidenenaltrexones as selective delta1 opioid receptor antagonists.
A series of 7-arylidinenaltrexones (2a-m) related to the prototypical delta1-selective antagonist, 7-benzylidenenaltrexone 1 (BNTX), have been synthesized in an effort to develop more selective ligands. Testing in smooth muscle preparations revealed that members of the series exhibited varying degrees of selectively for delta receptors, with the o-methoxy (2e) and o-chloro (2j) congeners being most potent and most selective (Ke approximately 0.8 nm). Evaluation of 1, 2e, and 2f sc in mice using the tail-flick procedure indicated that they are selective delta1 opioid receptor antagonists in the lower dose range. At high doses these ligands, including BNTX, exhibited decreased delta1 selectivity due to increases in the ED50 ratios of [D-Ser2,Leu5]enkephalin-Thr6 and morphine. It is concluded that 2e and 2f possess in vivo selectivity similar to that of BNTX, but are less potent as delta1 antagonists.
Ohkawa
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Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Portoghese
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D000818:Animals; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010147:Pain Measurement; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013623:Tail; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C115075:7-(2-methoxybenzylidene)naltrexone; C115076:7-(4-methylbenzylidene)naltrexone; D001597:Benzylidene Compounds; D008024:Ligands; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; C077358:7-benzylidenenaltrexone; D009271:Naltrexone