Weatherspoon J K, Gonzalez-Alvear G M, Werling L L
Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA.
Eur J Pharmacol. 1997 May 20;326(2-3):133-8. doi: 10.1016/s0014-2999(97)85407-6.
The binding profile of the sigma2 receptor ligand endo-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-2,3-dihydro-(1-methyl)eth yl-2-oxo-1H-benzimidazole-1-carboxamidehydrochloride (BIMU-8) had previously been determined, but its agonist/antagonist status at sigma2 receptors had not been identified. We therefore investigated the effects of BIMU-8 for its ability to regulate the stimulated release of [3H]norepinephrine from slices of guinea pig hippocampus. BIMU-8 alone, at a concentration chosen to occupy 50% of sigma2 receptors, had no significant effect on N-methyl-D-aspartate (NMDA)-stimulated release of [3H]norepinephrine. We have shown previously that the sigma receptor agonist (+)-pentazocine inhibits NMDA-stimulated release in a concentration-dependent manner, producing a biphasic inhibition curve. Similarly, the sigma receptor agonist 1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl )cyclohexylamine (BD737) produced a broad inhibition curve. The inhibition by low concentrations of (+)-pentazocine or BD737 that selectively activated sigma1 receptors was reversed by the sigma1-selective receptor antagonist (1-(cyclopropylmethyl)-4-2'-oxoethyl)piperidine HBr (DuP 734). In the current study, when the sigma1 component of inhibition by (+)-pentazocine was blocked by DuP 734, the remaining component of inhibition mediated by sigma2 receptors was reversed by BIMU-8. Our results suggest that (1) BIMU-8 is an antagonist at sigma2 receptors and that (2) sigma2 receptors contribute to regulation of norepinephrine release in guinea pig hippocampus.
此前已确定了σ2受体配体内-N-(8-甲基-8-氮杂双环[3.2.1]辛-3-基)-2,3-二氢-(1-甲基)乙基-2-氧代-1H-苯并咪唑-1-甲酰胺盐酸盐（BIMU-8）的结合图谱，但其在σ2受体上的激动剂/拮抗剂状态尚未明确。因此，我们研究了BIMU-8调节豚鼠海马切片中[3H]去甲肾上腺素刺激释放的能力。单独使用BIMU-8时，在选择占据50%σ2受体的浓度下，对N-甲基-D-天冬氨酸（NMDA）刺激的[3H]去甲肾上腺素释放没有显著影响。我们之前已经表明，σ受体激动剂(+)-喷他佐辛以浓度依赖的方式抑制NMDA刺激的释放，产生双相抑制曲线。同样，σ受体激动剂1S,2R-(-)-顺式-N-[2-(3,4-二氯苯基)乙基]-N-甲基-2-(1-吡咯烷基)环己胺（BD737）产生了一条宽抑制曲线。选择性激活σ1受体的低浓度(+)-喷他佐辛或BD737的抑制作用被σ1选择性受体拮抗剂(1-(环丙基甲基)-4-(2'-氧代乙基)哌啶HBr（DuP 734）逆转。在当前研究中，当(+)-喷他佐辛的抑制作用中的σ1成分被DuP 734阻断时，由σ2受体介导的剩余抑制成分被BIMU-8逆转。我们的结果表明：（1）BIMU-8是σ2受体的拮抗剂；（2）σ2受体有助于调节豚鼠海马中的去甲肾上腺素释放。
