Danso-Danquah R, Bai X, Zhang X, Mascarella S W, Williams W, Sine B, Bowen W D, Carroll F I
Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 1995 Jul 21;38(15):2978-85. doi: 10.1021/jm00015a022.
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.
本文介绍了几种（+）-和（-）-2-苄基-和2-二甲基烯丙基-2'-取代-5,9α-二甲基-6,7-苯并吗啡烷（3和4）的合成以及与σ1和σ2的结合特性。与先前报道的2-取代-5,9α-二甲基-2'-羟基-6,7-苯并吗啡烷（N-取代-N-去甲左啡诺）的结合数据一致，所有（1S,5S,9S）-（+）-异构体对σ1位点的亲和力均高于相应的（1R,5R,9R）-（-）-异构体。用2'-NH2和2'-N（CH3）2分别取代（+）-2-苄基-5,9α-二甲基-2'-羟基-6,7-苯并吗啡烷[（+）-1f]的2'-羟基[分别为（+）-3b和（+）-3c]，对σ1的Ki值影响很小。将（+）-1f的2'-羟基换成H、F、Cl、Br、I、NHAc或NHSO2CH3，导致效价损失5倍或更多。相反，用2'-H或2'-F基团取代（+）-2-（二甲基烯丙基）-5,9α-二甲基-2'-羟基-6,7-苯并吗啡烷[（+）-1b，（+）-喷他佐辛]的2'-羟基，效价提高了2倍。将（+）-1f转化为其2'-脱氧类似物（+）-2d，亲和力损失27.5倍。这表明（+）-1f和其他N-取代苯并吗啡烷类似物可能以不同方式与单个σ1受体结合，或者与不同的σ1受体结合。（-）-喷他佐辛[（-）-1b]及其2'-氟类似物，（-）-2-（二甲基烯丙基）-5,9α-二甲基-2'-氟-6,7-苯并吗啡烷[（-）-4a]对σ2结合位点显示出最高的效价。
