Novel naphthyloxy derivatives – Potent histamine H3 receptor ligands. Synthesis and pharmacological evaluation
作者:Dorota Łażewska、Maria Kaleta、Stefanie Hagenow、Szczepan Mogilski、Gniewomir Latacz、Tadeusz Karcz、Annamaria Lubelska、Ewelina Honkisz、Jadwiga Handzlik、David Reiner、Grzegorz Satała、Barbara Filipek、Holger Stark、Katarzyna Kieć-Kononowicz
DOI:10.1016/j.bmc.2018.04.023
日期:2018.5
A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H3 receptor affinity. Most compounds showed high affinities with Ki values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H3 receptor with a Ki value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP
合成了一系列的1-和2-萘氧基衍生物,并评估了组胺H3受体的亲和力。大多数化合物显示出高亲和力,Ki值低于100 nM。最有效的配体1-(5-(萘-1-基氧基)戊基)ep庚烷(11)对组胺H3受体表现出高亲和力,Ki值为21.9 nM。在体外cAMP分析中(IC50 = 312 nM)和在大鼠成药模型中体内(ED50 = 3.68 nM)都证实了11的拮抗剂行为。此外,化合物11对东碱引起的小鼠记忆力减退(剂量为10和15 mg / kg)具有积极作用,在福尔马林试验中对ED50 = 30.6 mg / kg(早期)和ED50 =的小鼠具有镇痛作用。 20.8 mg / kg(晚期)。另一种有趣的化合物是1-(5-(萘-1-基氧基)戊基)哌啶(13; H3R Ki = 53.9 nM),被美国国家神经系统疾病和中风研究所/美国国立卫生研究院接受抗惊厥筛查计划。筛选是在最大电击癫痫发作(ME