Rao Tadimeti S, Reid Richard T, Correa Lucia D, Santori Emily M, Gardner Michael F, Sacaan Aida I, Lorrain Daniel, Vernier Jean-Michel
Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA.
Brain Res. 2003 Oct 3;986(1-2):71-81. doi: 10.1016/s0006-8993(03)03174-3.
SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which is active in rodent and primate models of cognition. In functional assays, SIB-1553A exhibits marked subtype selectivity for nAChRs as compared to nicotine. In addition SIB-1553A also exhibits affinities to histaminergic (H3) and serotonergic (5-HT1 and 5HT2) receptors and sigma binding sites. In the present investigation, we characterized SIB-1553A-induced neurotransmitter release in vivo. Following subcutaneous injection (s.c., 10 mg/kg), SIB-1553A rapidly entered the brain achieving concentration of approximately 20 microM 15 min post-injection and was eliminated from plasma with a terminal half-life of approximately 32 min. In freely moving rats, SIB-1553A (1-40 mg/kg, s.c.), markedly increased ACh release in the hippocampus and prefrontal cortex. In both regions, the magnitude of SIB-1553A-induced ACh release was greater than that seen with the prototypical nAChR agonist, nicotine (0.4 mg/kg, s.c.). Both isomers of SIB-1553A induced similar levels of increase in hippocampal ACh release. Increased hippocampal ACh release was also observed following oral administration of SIB-1553A (40 mg/kg) or after local perfusion into the hippocampus (1 mM). SIB-1553A-induced hippocampal ACh release was significantly attenuated by two nAChR antagonists, mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), and by the dopamine (DA) (D1) antagonist, SCH-23390, arguing that ACh release, in part, involves activation of nAChRs and a permissive DA synapse. In contrast to its robust effects on ACh release, SIB-1553A (40 mg/kg, s.c.) modestly increased striatal DA release (approximately 180% of baseline). Due to the proposed role of cholinergic pathways in learning and memory, the neurochemical profile of SIB-1553A suggests a potential for it to treat cognitive dysfunction.
SIB - 1553A（（±）-4 - [2 - （1 - 甲基 - 2 - 吡咯烷基）乙基]苯硫酚盐酸盐）是一种神经元烟碱型乙酰胆碱受体（nAChR）配体，在啮齿动物和灵长类动物认知模型中具有活性。在功能测定中，与尼古丁相比，SIB - 1553A对nAChRs表现出显著的亚型选择性。此外，SIB - 1553A对组胺能（H3）和5 - 羟色胺能（5 - HT1和5HT2）受体以及σ结合位点也具有亲和力。在本研究中，我们对SIB - 1553A在体内诱导的神经递质释放进行了表征。皮下注射（10 mg/kg）后，SIB - 1553A迅速进入大脑，注射后15分钟达到约20μM的浓度，并以约32分钟的终末半衰期从血浆中消除。在自由活动的大鼠中，SIB - 1553A（1 - 40 mg/kg，皮下注射）显著增加海马体和前额叶皮质中的乙酰胆碱（ACh）释放。在这两个区域，SIB - 1553A诱导的ACh释放幅度大于典型nAChR激动剂尼古丁（0.4 mg/kg，皮下注射）所观察到的幅度。SIB - 1553A的两种异构体诱导海马体ACh释放增加的水平相似。口服SIB - 1553A（40 mg/kg）或局部灌注到海马体（1 mM）后，也观察到海马体ACh释放增加。两种nAChR拮抗剂美加明（MEC）和二氢β - 刺桐碱（DHbetaE）以及多巴胺（DA）（D1）拮抗剂SCH - 23390可显著减弱SIB - 1553A诱导的海马体ACh释放，这表明ACh释放部分涉及nAChRs的激活和允许性DA突触。与它对ACh释放的强烈作用相反，SIB - 1553A（40 mg/kg，皮下注射）适度增加纹状体DA释放（约为基线的180%）。由于胆碱能通路在学习和记忆中所提出的作用，SIB - 1553A的神经化学特征表明它具有治疗认知功能障碍的潜力。
