(2-exo-3-endo)-2-Aryltropane-3-carboxylic esters, a new class of narcotic antagonists

Tropanes 4 bearing an exo aromatic group on carbon-2, an endo-carbomethoxy group on carbon-3, and either a methyl group or a hydrogen on the nitrogen were found to be narcotic antagonists which were devoid of demonstrable analgesic activity. The activity resided in the 1S enantiomer. Compound 4 (R = m-hydroxyphenyl) showed an AD50 of 0.37 mg/kg sc and 1.8 mg/kg po (rats) as an antagonist in the Harris-Pierson modification of the D'Amour-Smith test. The tropane esters for this study were prepared by a Grignard reaction which gave essentially complete 1,4-addition in the absence of copper salts. Nearly equal quantities of esters epimeric at carbon-3 were formed.