Potent MOR Agonists from 2'-Hydroxy-5,9-dimethyl- N -phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N -Phenethylnormetazocine.

(-)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para -OH or ortho -F substituent in the aromatic ring of the N -phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1 R ,5 R ,9 R )-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1 R ,5 R ,9 R )-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N -phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho , meta , or para position in the aromatic ring of the N -phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N -phenethyl moiety was also modified by increasing chain length to form a N -phenylpropyl side chain with and without a para -nitro moiety, and by an N -cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N -phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para -nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC 50 = 12 nM), and was fully efficacious (%E max = 102%) in the cAMP assay. Retention of the N -phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (-)- N -phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized.