Department of Synthesis and Technology of Drugs, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland.
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
ACS Chem Neurosci. 2024 Mar 20;15(6):1206-1218. doi: 10.1021/acschemneuro.3c00800. Epub 2024 Mar 5.
This study examines the properties of a novel series of 4-oxypiperidines designed and synthesized as histamine HR antagonists/inverse agonists based on the structural modification of two lead compounds, viz., and . The products are intended to maintain a high affinity for HR while simultaneously inhibiting AChE or/and BuChE enzymes. Selected compounds were subjected to HR radioligand displacement and HR functional assays. Some of the compounds showed nanomolar affinity. The most promising compound in the naphthalene series was , which contained a benzyl moiety at position 1 of the piperidine ring and displayed 12.5 nM affinity at the HR and the highest inhibitory activity against AChE (IC = 1.537 μM). Eight compounds showed over 60% BuChE inhibition and hence were qualified for the determination of the IC value at BuChE; their values ranged from 0.559 to 2.655 μM. Therapy based on a multitarget-directed ligand combining HR antagonism with additional AChE/BuChE inhibitory properties might improve cognitive functions in multifactorial Alzheimer's disease.
本研究考察了一系列新型 4-氧代哌啶的性质，这些化合物是根据两个先导化合物（即[化合物 1]和[化合物 2]）的结构修饰设计和合成的，作为组胺 HR 拮抗剂/反向激动剂。这些产物旨在保持对 HR 的高亲和力，同时抑制 AChE 或/和 BuChE 酶。选择的化合物进行了 HR 放射性配体置换和 HR 功能测定。一些化合物表现出纳摩尔亲和力。在萘系列中最有前途的化合物是[化合物 11]，它在哌啶环的 1 位含有苄基部分，在 HR 上显示出 12.5 nM 的亲和力，对 AChE 的抑制活性最高（IC = 1.537 μM）。有 8 种化合物对 BuChE 的抑制率超过 60%，因此有资格确定其在 BuChE 上的 IC 值；它们的值范围从 0.559 到 2.655 μM。基于一种多靶点定向配体的治疗方法，将 HR 拮抗作用与额外的 AChE/BuChE 抑制特性相结合，可能会改善多因素阿尔茨海默病的认知功能。
