Suzuki T, Hirooka K, Kanda K, Uesaka H, Hirooka H, Furusawa K
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan.
Biol Pharm Bull. 1998 Jul;21(7):704-9. doi: 10.1248/bpb.21.704.
The neurochemical effects of SK-946, N-[2-(1-azabicyclo[3,3,0]octan-5-yl)ethyl]2-nitroaniline fumarate, were investigated in an attempt to elucidate cognition activating properties. In rat brain cortical membranes and in cloned human receptors expressed in Sf9 cells, SK-946 had submicromolar affinities for muscarinic receptors with a moderate selectivity for M1 (m1) sites. Although no increase in the antagonist (N-methylscopolamine)/agonist (oxotremorine-M) binding ratio was observed, SK-946 exhibited a partial agonistic effect on receptor-stimulated phosphoinositide hydrolysis in primary cultured rat fetal hippocampal cells. Heterogeneous, reversible and concentration-dependent excitations of the hippocampal neuronal cells treated with SK-946 (10(-5)-10(-3) M) were confirmed as increases in cytosolic Ca2+ concentrations measured in Fura-PE3 preloaded cells. Furthermore, SK-946 (>10(-5) M) increased [3H]myo-inositol uptake into the hippocampal cells. On the other hand, SK-946 had no effect on adenylate cyclase activities in primary cultured rat heart cells, and showed a weak antagonistic effect on carbachol-induced adenylate cyclase inhibition, suggesting that it is an M2 antagonist. Using in vivo microdialysis, it was found that relatively low concentrations (<10(-7) M) of SK-946 increased acetylcholine release and decreased choline content in that hippocampal area in rats. These results suggest that SK-946 accelerates muscarinic neuronal transmission in the central nervous system.
为阐明其认知激活特性，对富马酸N-[2-(1-氮杂双环[3,3,0]辛烷-5-基)乙基]2-硝基苯胺（SK-946）的神经化学效应进行了研究。在大鼠脑皮质膜以及在Sf9细胞中表达的克隆人受体中，SK-946对毒蕈碱受体具有亚微摩尔亲和力，对M1（m1）位点具有中等选择性。尽管未观察到拮抗剂（N-甲基东莨菪碱）/激动剂（氧化震颤素-M）结合率增加，但SK-946对原代培养的大鼠胎儿海马细胞中受体刺激的磷酸肌醇水解表现出部分激动作用。用SK-946（10⁻⁵ - 10⁻³ M）处理的海马神经元细胞的异质性、可逆性和浓度依赖性兴奋被确认为在预先加载Fura-PE3的细胞中测量的胞质Ca²⁺浓度增加。此外，SK-946（>10⁻⁵ M）增加了海马细胞对[³H]肌醇的摄取。另一方面，SK-946对原代培养的大鼠心脏细胞中的腺苷酸环化酶活性没有影响，并且对卡巴胆碱诱导的腺苷酸环化酶抑制表现出弱拮抗作用，表明它是一种M2拮抗剂。使用体内微透析发现，相对低浓度（<10⁻⁷ M）的SK-946可增加大鼠海马区的乙酰胆碱释放并降低胆碱含量。这些结果表明，SK-946可加速中枢神经系统中毒蕈碱神经元传递。
