Derivatives of flavonepenthone: Kappa opioid receptor selectivity in an N-methylmorphinan

To extend our investigation of analogs of the orvinols incorporating phenyl groups constrained in appropriately located fixed conformations, a series of analogs of flavonepenthone have been prepared and evaluated in opioid binding assays. Acid-catalyzed rearrangement of phenyldihydrothevinone gave a 7:1 mixture of (E)- and (Z)-isomers; the corresponding orvinol gave a corresponding 9:1 mixture. The 3,4-substitution pattern in the major isomer was manipulated to give a series of analogs for evaluation. Surprisingly, the flavonepenthone analogs showed selectivity for κ opioid receptors, and the (E)-4-hydroxy-3-methoxy isomer with K(i)(κ) = 0.14 nM and selectivity κ/δ = 40 and κ/μ = 32 is, to our knowledge, the most selective N- methylmorphinan derivative so far reported. It will be the subject of a full pharmacological evaluation.