Synthesis, opioid receptor binding, and functional activity of 5′-substituted 17-cyclopropylmethylpyrido[2′,3′:6,7]morphinans

A series of naltrexone-derived pyridomorphinans possessing various substituents at the 5′-position on the pyridine ring were synthesized and evaluated for opioid receptor binding in rodent brain membranes and functional activity in smooth muscle preparations. While the introduction of aromatic 1-pyrrolyl group (6h) improved the δ affinity and δ antagonist potency of the parent compound (3), the introduction of guanidine group (6i) transformed it to a κ selective ligand in opioid receptor binding and [³⁵S]GTP-γ-S functional assays.