Novel ligands for the opioid receptors: Synthesis and structure-activity relationships among 5′-aryl and 5′-heteroaryl 17-cyclopropylmethyl-4,5α-epoxypyrido[2′,3′:6,7]morphinans

A series of pyridomorphinans possessing an aryl (10a-s) or heteroaryl (11a-h) substituent at the 5′-position of the pyridine ring of 17-cyclopropylmethyl-4,5α-epoxypyrido[2′,3′:6,7]morphinan was synthesized and evaluated for binding and functional activity at the opioid δ, μ, and κ receptors. All of these pyridomorphinans bound with higher affinity at the δ site than at μ or κ sites. The binding data on isomeric compounds revealed that there exists greater bulk tolerance for substituents placed at the o-position of the phenyl ring than at m- or p-positions. Among the ligands examined, the 2-chlorophenyl (10l), 2-nitrophenyl (10n), 2-pyridyl (11a), and 4-quinolinyl (11g) compounds bound to the δ receptor with subnanomolar affinity. Compound 10c with the p-tolyl substituent displayed the highest μδ selectivity (ratio=42) whereas compound 10l with the 2-chlorophenyl substituent displayed the highest κδ selectivity (ratio=23). At 10 μM concentration, the in vitro functional activity determined using [³⁵S]GTP-γ-S binding assays showed that all of the compounds were antagonists devoid of any significant agonist activity at the δ, μ, and κ receptors. Antagonist potency determinations of three selected ligands revealed that the p-tolyl compound 10c is a potent δ selective antagonist. In the [ ³⁵S]GTP-γ-S assays this compound had a functional antagonist K_i value of 0.2, 4.52, and 7.62 nM at the δ, μ, and κ receptors, respectively. In the smooth muscle assays 10c displayed δ antagonist potency with a K_e value of 0.88 nM. As an antagonist, it was 70-fold more potent at the δ receptors in the MVD than at the μ receptors in the GPI. The in vitro δ antagonist profile of this pyridomorphinan 10c resembles that of the widely used δ selective antagonist ligand naltrindole.