Synthesis, Opioid Receptor Binding, and Biological Activities of Naltrexone-Derived Pyrido- and Pyrimidomorphinans

A series of pyrido- and pyrimidomorphinans (6a−h and 7a−g) were synthesized from naltrexone and evaluated for binding and biological activity at the opioid receptors. The unsubstituted pyridine 6a displayed high affinities at opioid δ, μ, and κ receptors with Ki values of 0.78, 1.5, and 8.8 nM, respectively. Compound 6a was devoid of agonist activity in the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations but was found to display moderate to weak antagonist activity in the MVD and GPI with Ke values of 37 and 164 nM, respectively. The pyrimidomorphinans in general displayed lower binding potencies and δ receptor binding selectivities than their pyridine counterparts. Incorporation of aryl groups as putative δ address mimics on the pyrido- and pyrimidomorphinan framework gave ligands with significant differences in binding affinity and intrinsic activity. Attachment of a phenyl group at the 4‘-position of 6a or the equivalent 6‘-position of 7a led to dramatic reduction in binding potencies ...