Effect of N-alkyl and N-alkenyl substituents in noroxymorphindole, 17-substituted-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7:2′,3′-indolomorphinans, on opioid receptor affinity, selectivity, and efficacy

The N-alkyl analogues (N-ethyl through N-heptyl), branched N-alkyl chain analogues (N-isopropyl, N-2-methylpropyl, and N-3-methylbutyl), and N-alkenyl analogues ((E)-N-3-methylallyl (crotyl), N-2-methylallyl, and N-3,3-dimethylallyl) were prepared in the noroxymorphindole series (17-substituted-6,7-dehydro-4,5 alpha -epoxy-3,12-dihydroxy-6,7:2 ' ,3 ' -indolomorphinans), and the effect of the N-substituent on opioid receptor affinity, selectivity, and efficacy was examined using receptor binding assays, [S-35]GTP gammaS efficacy determinations, and smooth muscle functional assays (electrically stimulated mouse vas deferens and guinea pig ileum). All of the compounds acted as opioid antagonists, including those with N-substituents which usually confer either weak agonist-antagonist behavior (N-ethyl) or potent opioid agonist activity (N-pentyl) in morphinan-like ligands which interact with the mu -receptor. Several N-substituted noroxymorphindoles were found to be more mu/delta -selective than naltrindole (NTI). The N-2-methylallylnoroxymorphindole, in particular, was found to be more selective than NTI in receptor binding assays (mu/delta = 1700 vs 120; kappa/delta = 810 vs 140), as an antagonist in the GTP gammaS assay (mu/delta = 170 vs 140; kappa/delta = 620 vs 160), and considerably more selective than NTI in the functional assays (mu/delta > 2200 vs 90), It also had high affinity for the delta -opioid receptor (K-i = 4.7 nM in the binding assay) and high antagonist potency (1.2 nM in the GTP gammaS assay; 8.9 nM in the MVD assay).