A novel class of 5-HT2A receptor antagonists: Aryl aminoguanidines

被引:22
作者
Bryant, HU
Nelson, DL
Button, D
Cole, HW
Baez, MB
Lucaites, VL
Wainscott, DB
Whitesitt, C
Reel, J
Simon, R
Koppel, GA
机构
[1] ELI LILLY & CO,CENT NERVOUS SYST RES,INDIANAPOLIS,IN 46285
[2] NIMH,CELL BIOL LAB,BETHESDA,MD 20892
关键词
serotonin; aryl aminoguanidine; 5-HT2A receptor antagonists;
D O I
10.1016/0024-3205(96)00449-3
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding studies with I-125 DOI On human 5-HT2A and 5-HT2C receptors and with H-3-5-HT on human 5-HT2B receptors demonstrated that, LY314228, and LY320954 displayed some selectivity for the 5-HT2A receptor. When compared to binding at other 5-HT2 receptor subtypes, LY314228 had an 18.6-fold greater affinity for the 5-HT2A site over the 5-HT2B site, and 2.6 fold greater at the 5.HT2C site. LY320954 displayed similar preference for 5-HT2A sites. Both compounds also inhibited 5-HT-induced paw swelling in rats, with ED(50)'s of 6.4 and 4.8 mg/kg (for LY314228 and LY320954, respectively). These studies offer evidence for a novel class of pharmacophores for the 5-HT2 receptor family which show greater relative affinities for the 5-HT2A receptor subclass.
引用
收藏
页码:1259 / 1268
页数:10
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