2,3-二氢二噻英和二噻庚因-1,1,4,4-四氧化物：人甘丙肽hGAL-1受体的小分子非肽拮抗剂。

2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides: small molecule non-peptide antagonists of the human galanin hGAL-1 receptor.

作者信息

Scott M K, Ross T M, Lee D H, Wang H Y, Shank R P, Wild K D, Davis C B, Crooke J J, Potocki A C, Reitz A B

机构信息

Drug Discovery Division, The R. W. Johnson Pharmaceutical Institute, Spring House, PA 19447, USA.

出版信息

Bioorg Med Chem. 2000 Jun;8(6):1383-91. doi: 10.1016/s0968-0896(00)00062-6.

DOI:10.1016/s0968-0896(00)00062-6

PMID:10896115

Abstract

The neuropeptide galanin modulates several physiological functions such as cognition, learning, feeding behavior, and depression, probably via the galanin 1 receptor (GAL-R1). Using an HTS assay based on 125I-human galanin binding to the human galanin-1 receptor (hGAL-R1), we discovered a series of 1,4-dithiin and dithiipine-1,1,4,4-tetroxides that exhibited binding affinity IC50's to hGAL-R1 ranging from 190 to 2700 nM. Two of the dithiepin analogues, 7 and 23, behaved pharmacologically as hGAL-R1 antagonists in secondary assays involving adenylate cyclase activity and GTP binding to G-proteins. Analogues 7 and 23 were also active in functional assays involving galanin, reversing the inhibitory effect of galanin on acetylcholine (ACh) release in rat brain hippocampal slices and electrically-stimulated guinea pig ileum twitch.

摘要

神经肽甘丙肽可能通过甘丙肽1型受体（GAL-R1）调节多种生理功能，如认知、学习、摄食行为和抑郁。我们使用基于125I-人甘丙肽与人甘丙肽-1型受体（hGAL-R1）结合的高通量筛选试验，发现了一系列1,4-二硫杂环己二烯和二硫杂环己二烯-1,1,4,4-四氧化物，它们对hGAL-R1的结合亲和力IC50范围为190至2700 nM。在涉及腺苷酸环化酶活性和GTP与G蛋白结合的二级试验中，两种二硫杂环己二烯类似物7和23在药理上表现为hGAL-R1拮抗剂。类似物7和23在涉及甘丙肽的功能试验中也具有活性，可逆转甘丙肽对大鼠脑海马切片中乙酰胆碱（ACh）释放和电刺激豚鼠回肠抽搐的抑制作用。