G-Protein biased opioid agonists: 3-hydroxy- N -phenethyl-5-phenylmorphans with three-carbon chain substituents at C9

A series of compounds have been synthesized with a variety of substituents based on a three-carbon chain at the C9-position of 3-hydroxy- -phenethyl-5-phenylmorphan (3-(2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol). Three of these were found to be μ-opioid receptor agonists in the inhibition of forskolin-induced cAMP accumulation assay and they did not recruit β-arrestin at all in the PathHunter assay and in the Tango assay. Compound (3-((1 ,5 ,9 )-2-phenethyl-9-propyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), (3-((1 ,5 ,9 )-9-(( )-3-hydroxyprop-1-en-1-yl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), and (3-((1 ,5 ,9 )-9-(2-hydroxypropyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol) were partial μ-agonists. Two of them had moderate efficacies ( 65%) and one had lower efficacy, and they were 5, 3, and 4 times more potent, respectively, than morphine . Computer simulations were carried out to provide a molecular basis for the high bias ratios of the C9-substituted 5-phenylmorphans toward G-protein activation.