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-dimethyl-6,7-benzomorphans (3 and 4) are presented. In agreement with previously reported binding data for 2-substituted 5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans (N-substituted-N-normetazocine), all (1S,5S,9S)-(+)-isomers showed higher affinity for the sigma 1 site than the corresponding (1R,5R,9R)-(-)-isomers. Replacement of the 2'-hydroxy group 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] had only a small effect on the sigma 1 Ki values. Changing the 2'-hydroxy 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 the 2'-hydroxy group of (+)-2-(dimethylallyl)-5,9 alpha-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 (+)-1f to its 2'-desoxy analogue (+)-2d resulted in a 27.5-fold loss in affinity. This suggests that (+)-1f and other N-substituted benzomorphan analogues may be binding to single sigma 1 receptors in a different way or to different sigma 1 receptors. (-)-Pentazocine [(-)-1b] and its 2'-fluoro analogue, (-)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-fluoro-6,7-benzomorphan [(-)-4a] showed the highest potency for the sigma 2 binding site.
Danso-Danquah
R
R
Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Bai
X
X
Zhang
X
X
Mascarella
S W
SW
Williams
W
W
Sine
B
B
Bowen
W D
WD
Carroll
F I
FI
D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001575:Benzomorphans; D017480:Receptors, sigma