Pyrrolomorphinans as delta opioid receptor antagonists. The role of steric hindrance in conferring selectivity.
A series of 2',3'-disubstituted pyrrolomorphinans (5a-i) were synthesized to determine the role of steric hindrance at mu and kappa receptors in promoting delta opioid receptor antagonist selectivity. In smooth muscle preparations, five members of the series (5a-c,e,f) possessed Ke values in the range 2-15 nM and were delta selective. Since the unsubstituted analogue 4 possessed delta antagonist potency of similar magnitude, but was not delta selective, it is suggested that the 2',3'-substitution confers delta selectivity by hindering the interaction of the pharmacophore at mu and kappa receptors, while not affecting delta receptors.
Farouz-Grant
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Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
Portoghese
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PS
D000818:Animals; D004558:Electric Stimulation; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D016314:Ethylketocyclazocine / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008956:Models, Chemical; D009019:Morphinans / Q000737:chemistry* / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
D009019:Morphinans; D011758:Pyrroles; D017465:Receptors, Opioid, delta; D016314:Ethylketocyclazocine; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine