Synthesis and σ binding properties of 2'-substituted 5,9α-dimethyl-6,7-benzomorphans
1995
The synthesis and σ1 and σ2 binding properties of several (+)- and (-)-2-benzyl- and 2-dimethylallyl-2'-substituted-5,9α-dimethyl-6,7-benzomorphans (3 and 4) are presented. In agreement with previously reported binding data for 2-substituted 5,9α-dimethyl-2'-hydroxy-6,7-benzomorphans (N-substituted-N-normetazocine), all (1S,5S,9S)-(+)-isomers showed higher affinity for the σ1 site than the corresponding (1R,5R,9R)-(-)-isomers. Replacement of the 2'-hydroxy group of (+)-2-benzyl-5,9α-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)-1f] with a 2'-NH 2 and 2'-N(CH 3 ) 2 [(+)-3b and (+)-3c, respectively] had only a small effect on the σ1 K i values. Changing the 2'-hydroxy group of (+)-If to an H, F, Cl, Br, I, NHAc, or NHSO 2 CH 3 resulted in a 5-fold or greater loss in potency. In contrast, replacement of the 2'-hydroxy group of (+)-2-(dimethylallyl)-5,9α-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)-1b, (+)-pentazocine] with a 2'-H or 2'-F group resulted in a 2-fold increase in potency. Conversion of (+)-If to its 2'-desoxy analogue (+)-2d resulted in a 27.5-fold loss in affinity. This suggests that (+)-If and other N-substituted benzomorphan analogues may be binding to single σ1 receptors in a different way or to different σ1 receptors. (-)-Pentazocine [(-)-1b] and its 2'-fluoro analogue, (-)-2-(dimethylallyl)-5,9α-dimethyl-2'-fluoro-6,7-benzomorphan [(-)-4a] showed the highest potency for the σ2 binding site.
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