7-Spiroindanyl derivatives of naltrexone and oxymorphone as selective ligands for delta opioid receptors.
A series consisting of spiroindanyl (5-7), benzospiroindanyl (8-10), and spiroperinaphthyl (11) derivatives of naltrexone and oxymorphone were synthesized in order to investigate the role of an orthogonal-oriented "address" for delta opioid receptors. All of the ligands exhibited a preference for delta receptors in vitro. The 7-benzospiroindanyl derivative 8 (BSINTX) was the most selective delta opioid receptor antagonist in vitro. In mice BSINTX antagonized the delta 1-selective agonist, [D-Pen2,D-Pen5]enkephalin without significantly affecting the antinociceptive potency of delta 2, mu, and kappa agonists. The results of this study are consistent with an orthogonally-oriented address favoring delta 1 activity.
Ohkawa
S
S
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
DiGiacomo
B
B
Larson
D L
DL
Takemori
A E
AE
Portoghese
P S
PS
D000698:Analgesia; D000700:Analgesics; D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D010111:Oxymorphone / Q000031:analogs & derivatives*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D014649:Vas Deferens
C106278:7-(5',6'-benzo-2'-spiroindanyl)naltrexone; D000700:Analgesics; D004745:Enkephalins; D008024:Ligands; D017465:Receptors, Opioid, delta; D013141:Spiro Compounds; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; D010111:Oxymorphone