Matsuno K, Nakazawa M, Okamoto K, Kawashima Y, Mita S
Central Research Laboratories, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
Eur J Pharmacol. 1996 Jun 13;306(1-3):271-9. doi: 10.1016/0014-2999(96)00201-4.
The binding profiles of SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), a novel sigma receptor ligand, to sigma 1 and sigma 2 receptor subtypes in guinea pig and rat brain membranes were evaluated. SA4503 showed a high affinity for the sigma 1 receptor subtype labeled by (+)-[3H]pentazocine (IC50 = 17.4 +/- 1.9 nM), while it had about 100-fold less affinity for the sigma 2 receptor subtype labeled by [3H]1,3-di(2-tolyl)guanidine ([3H]DTG) in the presence of 200 nM (+)-pentazocine. SA4503 showed little affinity for 36 other receptors, ion channels and second messenger systems. The inhibition curves of SA4503 for (+)-[3H]pentazocine binding were shifted to the right in the presence of guanosine 5'-o-(3-thiotriphosphate) (GTP gamma S), as similar to those of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and (+)-pentazocine, sigma 1 receptor agonists. SA4503 significantly increased the KD value, but did not affect the Bmax value for specific (+)-[3H]pentazocine binding. These results indicated that SA4503 is a potent and selective agonist for the sigma 1 receptor subtype in the brain. In addition, SA4503 inhibited specific (+)-[3H]pentazocine binding in a competitive manner.
对新型σ受体配体SA4503（1-(3,4-二甲氧基苯乙基)-4-(3-苯基丙基)哌嗪二盐酸盐）与豚鼠和大鼠脑膜中σ1和σ2受体亚型的结合情况进行了评估。SA4503对由(+)-[3H]喷他佐辛标记的σ1受体亚型表现出高亲和力（IC50 = 17.4 +/- 1.9 nM），而在存在200 nM(+)-喷他佐辛的情况下，它对由[3H]1,3-二(2-甲苯基)胍（[3H]DTG）标记的σ2受体亚型的亲和力约低100倍。SA4503对其他36种受体、离子通道和第二信使系统几乎没有亲和力。在存在鸟苷5'-O-(3-硫代三磷酸)（GTPγS）的情况下，SA4503对(+)-[3H]喷他佐辛结合的抑制曲线向右移动，类似于σ1受体激动剂(+)-3-(3-羟基苯基)-N-(1-丙基)哌啶((+)-3-PPP)和(+)-喷他佐辛的抑制曲线。SA4503显著增加了KD值，但不影响特异性(+)-[3H]喷他佐辛结合的Bmax值。这些结果表明，SA4503是脑中σ1受体亚型的强效选择性激动剂。此外，SA4503以竞争性方式抑制特异性(+)-[3H]喷他佐辛结合。
