Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based Opioid Receptor (OR) Agonists Using the Strategy of Bridging

kappa opioid receptor (kappa OR) is a subtype of opioid receptors, and there are two major kappa OR agonists currently available, morphinans and arylacetamides, which are structurally distinct from each other. Numerous efforts had been made to correlate these series of compounds in order to establish a consensus binding pattern for kappa OR agonists. Unfortunately, no morphinan-based agent with an arylacetamidyl substituent has been identified as a kappa OR agonist with a pharmacological profile similar to arylacetamides. Since the recently described morphinan-based compound SLL-039 was identified as a selective and potent kappa OR agonist that contains a unique benzamidyl substituent in structure similar to arylacetamides, numerous arylacetamidyl substituents were introduced to this scaffold to examine whether the structure-activity relationships (SARs) of arylacetamides in conferring kappa OR agonistic activities could be reproduced by these analogues. Thus, a series of Ncyclopropylmethyl-7-alpha-arylacetamidylphenyl-6,14-endoethanotetrahydronorthebaine analogues were designed, synthesized, and assayed for biological activities. Among these compounds, compound 4j with a 3',4'-dimethylphenylacetamidyl substituent showed a single digit low nanomolar affinity to the kappa OR and relatively high subtype selectivity in binding assays, but this profile was not reproduced in functional assays. In contrast, compound 4i displayed moderately selective kappa OR agonistic activities in functional assays, which was inconsistent with its nonselective nature in binding assays. Overall, introduction of an arylacetamidyl substituent to the morphinan-based scaffold was associated with pharmacological diversity in both binding and functional activities on opioid receptors in vitro. The resultant SARs were inconsistent with that of classical arylacetamides as kappa OR agonists, despite bearing a similar arylacetamidyl substituent in the structure. Therefore, the arylacetamidyl substituent of the morphinan-based scaffold was found to be disconnected from that of arylacetamides in conferring kappa OR activities.