SYNTHESIS AND SIGMA-BINDING-PROPERTIES OF 2'-SUBSTITUTED 5,9-ALPHA-DIMETHYL-6,7-BENZOMORPHANS

The synthesis and sigma 1 and sigma 2 binding properties of several ()- and (-)-2-benzyl- and 2-dimethylallyl-2'-substituted-5,9 alpha-dime thyl-6,7-benzomorphans (3 and 4) are presented. In agreement with prev iously reported binding data for 2-substituted 5,9 alpha-dimethyl-2'-h ydroxy-6,7-benzomorphans (N-substituted-N-normetazocine), all (1S,5S,S S)-(+)-isomers showed higher affinity for the sigma 1 site than the co rresponding (1R,5R,9R)-(-)-isomers. Replacement of the 2'-hydroxy grou p of (+)-2-benzyl-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)- 1f] with a 2'-NH2 and 2'-N(CH3)(2) [(+)-3b and (+)-3c, respectively] h ad only a small effect on the sigma 1 K-i values. Changing the 2'-hydr oxy group of (+)-1f to an H, F, Cl, Br, I, NHAc, or NHSO2CH3 resulted in a 5-fold or greater loss in potency. In contrast, replacement of th e 2'-hydroxy group of (+)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-hydr oxy-6,7-benzomorphan [(+)-1b, (+)-pentazocine] with a 2'-H or 2'-F gro up resulted in a 2-fold increase in potency. Conversion of (+)-1f to i ts 2'-desoxy analogue (+)-2d resulted in a 27.5-fold loss in affinity. This suggests that (+)-1f and other N-substituted benzomorphan analog ues may be binding to single al receptors in a different way or to dif ferent sigma 1 receptors. (-)-Pentazocine [(-)-1b] and its 2'-fluoro a nalogue, (-)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-fluoro-6,7-benzom orphan [(-)-4a] showed the highest potency for the sigma 2 binding sit e.