chemistry of opium alkaloids. part 44: Synthesis and opioid receptor binding profile of substituted ethenoisomorphinans and ethenomorphinans Original Research Article

7- And 8-substituted 6α,14α-ethenoisomorphinans were synthesized by reaction of properly substituted morphinan-6,8-dienes (analogues of thebaine) with methyl vinyl ketone or ethyl acrylate. Reaction with the appropriate Grignard reagent gave the 7- and 8-dialkylmethanols, respectively. Cleavage of the 3-methyl ether with KOH/glycol or boron tribromide afforded the 3-hydroxyl derivatives. In general, the compounds with the ethoxycarbonyl or dimethylmethanol substituent at the 8α-position showed lower affinity for the μ, κ, and δ opioid receptor subtypes than the corresponding 7α- and 7β-substituted compounds. Introduction of a chloro substituent in position 18 increased the potency significantly. The 7-substituent could be connected to the 18-position without loss of affinity. 5β-alkyl substitution of 6α,14α-ethenoisomorphinans led to a decrease in affinity for the three opioid receptor subtypes. In the 5β-methyl series the affinity for the μ and δ receptors increased from 7α-dimethylmethanol to 7α-methylhexylmethanol. In the 5β-alkyl series, the affinity for the μ-receptor could be increased by connecting the 5- and 7-substituents, yielding a compound with high μ-selectivity. The new 6β,14β-ethenomorphinans did not show affinity for any of the opioid receptors, in accordance with the inactivity earlier found in in vivo experiments.