Synthesis and analgetic activity of some 5-aryl-2azabicyclo[3.2.1]octanes

A series of 5-aryl-2-azabicyclo[3.2.1]octanes II has been synthesized and evaluated for analgetic agonist-antagonist activity. These compounds can be regarded as five-membered, conformationally more rigid analogues of the potent agonist-antagonist (-)-5-(3-hydroxyphenyl)-2-methylmorphan (I). Several of these compounds have demonstrated marked analgesic potency comparable to morphine in the mouse writhing assay. Structure-activity correlations, generated by varying N-substitution and O-acetylation of the phenolic function, seem to indicate that optimum activity is associated with an arylethyl side chain attached to the basic nitrogen. Among the most interesting compounds in this series are the phenethyl analogue 31 and its O-acetate 39; the former shows the profile of a well-balanced analgetic-antagonist virtually devoid of physical dependence liability as demonstrated in the rat infusion test.