4'-Arylpyrrolomorphinans: effect of a pyrrolo-N-benzyl substituent in enhancing delta-opioid antagonist activity.
A new method for the preparation of N-benzylpyrrolomorphinans has been developed. Thus Michael reaction of the benzylimines of oxycodones and oxymorphones with nitrostyrenes gave a series of 4'-aryl-N-benzylpyrrolomorphinans. These were selective delta antagonists of much higher in vitro potency (with 5a having K(e) delta = <1 nM) than their binding affinities predicted. In mice in vivo assays 5a showed good delta antagonist activity in the anti-writhing analgesic assay and also inhibited delta agonist-induced convulsant activity.
Srivastava
Sanjay K
SK
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Husbands
Stephen M
SM
Aceto
Mario D
MD
Miller
Carl N
CN
Traynor
John R
JR
Lewis
John W
JW
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship; D014162:Transfection; D014649:Vas Deferens / Q000378:metabolism
D008024:Ligands; D009019:Morphinans; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta