Chemistry of opium alkaloids. Part 44: Synthesis and opioid receptor binding profile of substituted ethenoisomorphinans and ethenomorphinans

7- And 8-substituted 6 alpha,14 alpha-ethenoisomorphinans were synthesized by reaction of properly substituted morpkinan-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 8 alpha-position showed lower affinity for the mu, kappa, and delta opioid receptor subtypes than the corresponding 7 alpha- and 7 beta-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. 5 beta-alkyl substitution of 6 alpha, 14 alpha-ethenoisomorphinans led to a decrease in affinity for the three opioid receptor subtypes. In the 5 beta-methyl series the affinity for the mu and delta receptors increased from 7 alpha-dimethylmethanol to 7 alpha-methylhexylmethanol. In the 5 beta-alkyl series, the affinity for the mu-receptor could be increased by connecting the 5- and 7-substituents, yielding a compound with high mu-selectivity. The new 6 beta,14 beta-ethenomorphinans did not show affinity for any of the opioid receptors, in accordance with the inactivity earlier found in in vivo experiments. (C) 1999 Elsevier Science Ltd. All rights reserved.