Electrophilic N-benzylnaltrindoles as delta opioid receptor-selective antagonists.
The N-benzyl group of N-benzylnaltrindole (1, BNTI), a potent and selective delta 2 opioid receptor antagonist, was employed as a scaffold to hold electrophilic moieties (isothiocyanate and haloacetamide) in an effort to obtain selective affinity labels (2-4 and 8-11). The corresponding acetamide derivatives (5-7) also were synthesized to serve as nonelectrophilic controls. The o- and p-isothiocyanates (2 and 4) and the haloamides (8-11) were selective delta opioid receptor antagonists in the mouse vas deferens (MVD) preparations, while the meta isomer 3 was a delta-selective full agonist (IC50 = 5 nM). The fact that the effect of 2 and 4 was found to increase as a function of time in MVD suggests a covalent mechanism for the wash resistant component. The m-isothiocyanate 3 was found to be a delta-selective and irreversible agonist in the MVD, and it is suggested that it may be covalently binding to an agonist recognition site. In the mouse abdominal stretch antinociceptive assay, compounds 2-4 and 9 were delta-selective antagonists but exhibited delta 2/delta 1 selectivity ratios than that of BNTI.
Korlipara
V L
VL
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
Takemori
A E
AE
Portoghese
P S
PS
D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects
C093324:N-benzylnaltrindole; D017465:Receptors, Opioid, delta; D009271:Naltrexone