Synthesis and sigma binding properties of 2'-substituted 5,9 alpha-dimethyl-6,7-benzomorphans.
Synthesis and sigma binding properties of 2'-substituted 5,9 alpha-dimethyl-6,7-benzomorphans.
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2-取代的 5,9 α-二甲基-6,7-苯并吗啡烷的合成和 σ 结合特性。
DOI：
10.1021/jm00015a022
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发表时间：
1995
影响因子：
7.3
通讯作者：
F. Carroll
中科院分区：
文献类型：
--
作者：
R. Danso;X. Bai;X. Zhang;S. Mascarella;W. Williams;B. Sine;W. Bowen;F. Carroll
报道了几种(+)-和(-)-2-苄基和2-二甲基烯丙基-2‘-取代-5，9-二甲基-6，7-苯并吗啉(3和4)的合成及其与sigma1和sigma2的结合性能。与先前报道的2-取代5，9-二甲基-2‘-羟基-6，7-苯并吗啉(N-取代-N-去甲基咪唑)的结合数据一致，所有(1S，5S，9S)-(+)-异构体对sigma 1位点的亲和力均高于相应的(1R，5R，9R)-(-)-异构体。用2‘-NH_2和2’-N(CH_3)_2[(+)-3b和(+)-3c]取代(+)-2-苄基-5，9-二甲基-2‘-羟基-6，7-苯并吗？将(+)-1f的2‘-羟基改变为H、F、Cl、Br、I、NHHAC或NHSO2CH3会导致效力损失5倍或更多。相反，用2‘-H或2’-F取代(+)-2-(二甲基烯丙基)-5，9-二甲基-2‘-羟基-6，7-苯并吗[(+)-1b，(+)-五唑啉]的2’-羟基可使效价提高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-取代苯并吗类似物可能以不同的方式与单一的sigma-1受体结合或与不同的sigma-1受体结合。(-)-五唑并[(-)-1b]及其2‘-氟类似物，(-)-2-(二甲基烯丙基)-5，9-二甲基-2’-氟-6，7-苯并吗？[(-)-4a]显示了最高的结合活性。
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.