Nguyen V H, Kassiou M, Johnston G A, Christie M J
Department of Pharmacology, University of Sydney, NSW, Australia.
Eur J Pharmacol. 1996 Sep 12;311(2-3):233-40. doi: 10.1016/0014-2999(96)00395-0.
Comparisons of binding parameters of 3H-pentazocine and [3H]1,3-di-o-tolylguanidine (DTG) at sigma binding sites in guinea pig and rat brain membranes demonstrated that 3H-pentazocine binds to a single high-affinity site, whereas [3H]DTG binds to two high-affinity sites in both species. The Kd values of the radioligands were similar in both types of membranes. However, the density of sigma 1 sites in guinea pig was significantly higher than that of rat. Novel trishomocubanes were tested for their affinities at sigma 1 and sigma 2 binding sites in guinea pig brain membranes using 3H-pentazocine and [3H]DTG as the radioligands. N-(4-Phenylbutyl)-3-hydroxy-4- azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecane (ANSTO-14) showed the highest affinity for the sigma 1 site (Ki = 9.4 nM) and 19-fold sigma 1/sigma 2 selectivity, as a result of increasing the alkyl chain between the cubane moiety and the aromatic ring. N-(3'-Fluorophenyl)methyl- 3-hydroxy-4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11]dodeca ne (ANSTO-19), displayed the highest affinity for sigma 2 sites (Ki = 19.6 nM) and 8-fold sigma 2/sigma 1 selectivity due to a fluoro substitution in the meta position of the aromatic ring. These represent structurally novel lead compounds, especially for the development of selective sigma 2 receptor ligands.
对豚鼠和大鼠脑膜中σ结合位点上³H-喷他佐辛和[³H]1,3-二邻甲苯基胍（DTG）结合参数的比较表明，³H-喷他佐辛与单一高亲和力位点结合，而[³H]DTG在两种动物中均与两个高亲和力位点结合。两种类型的膜中放射性配体的Kd值相似。然而，豚鼠中σ1位点的密度显著高于大鼠。使用³H-喷他佐辛和[³H]DTG作为放射性配体，对新型三降莰烷在豚鼠脑膜中σ1和σ2结合位点的亲和力进行了测试。N-(4-苯基丁基)-3-羟基-4-氮杂六环[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]十二烷（ANSTO-14）对σ1位点表现出最高亲和力（Ki = 9.4 nM），并且由于增加了立方烷部分与芳环之间的烷基链，具有19倍的σ1/σ2选择性。N-(3'-氟苯基)甲基-3-羟基-4-氮杂六环[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]十二烷（ANSTO-19）对σ2位点表现出最高亲和力（Ki = 19.6 nM），并且由于芳环间位的氟取代，具有8倍的σ2/σ1选择性。这些代表了结构新颖的先导化合物，特别是用于开发选择性σ2受体配体。
