Asymmetric synthesis of 9-alkyl-2-benzyl-6 7-benzomorphans: Characterization as novel sigma receptor ligands

A convenient enantioselective synthesis of (1R,5R,9R)- and (1S,5S,9S)-9-alk yl-2-benzyl-6,7-benzomorphans (2a-c) which starts with naphthaldehyde is de scribed. These compounds were designed to gain additional information on th e structure-a binding relationship of the 6,7-benzomorphan class of a ligan ds. In contrast to pentazocine and most 6,7-benzomorphans, the (1R,5R,9R)-i somers of 2a-c showed greater affinity for the al receptor than the (1S,5S, 9S)isomers. Despite reversal of enantioselectivity at the ax sites, moderat e affinity and enantioselectivity at the sigma(2) sites [greater affinity f or (1R,5R,9R)-isomers than (1S,5S,9S)-isomers] were maintained. A compariso n of the binding affinities of 2a-e to the more conformationally flexible t rans-2-alkyl-1-benzaminoethyl-1,2-dihydronaphthalenes (10a-c) suggested tha t the relatively rigid structure of 2a-c played an important part in their al binding properties. These compounds, particularly (1R,5R,SR)-2-benzyl-9- methyl-6,7-benzomorphan [(-)-2a], which has a Ki value of 0.96 nM, will be useful in further characterization of the al receptor.