Bucki Adam, Marcinkowska Monika, Śniecikowska Joanna, Więckowski Krzysztof, Pawłowski Maciej, Głuch-Lutwin Monika, Gryboś Anna, Siwek Agata, Pytka Karolina, Jastrzębska-Więsek Magdalena, Partyka Anna, Wesołowska Anna, Mierzejewski Paweł, Kołaczkowski Marcin
Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna Street, 30-688 Kraków, Poland.
Institute of Psychiatry and Neurology , 9 Sobieskiego Street, 02-957 Warsaw, Poland.
J Med Chem. 2017 Sep 14;60(17):7483-7501. doi: 10.1021/acs.jmedchem.7b00839. Epub 2017 Aug 18.
The most troublesome aspects of behavioral and psychological symptoms of dementia (BPSD) are nowadays addressed by antidepressant, anxiolytic, and antipsychotic drugs, often administered off-label. Considering their modest effectiveness in dementia patients, the increased risk of adverse events and cognitive decline, there is an unmet need for well-tolerated and effective therapy of BPSD. We designed and synthesized multifunctional ligands characterized in vitro as high-affinity partial agonists of DR, antagonists of 5-HTR, and blockers of SERT. Moreover, the molecules activated 5-HTR and blocked 5-HTR while having no relevant affinity for off-target MR and hERG channel. Compound 16 (N-{2-[4-(5-chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl}-3-methylbenzene-1-sulfonamide) exhibited a broad antipsychotic-, antidepressant-, and anxiolytic-like activity, not eliciting motor impairments in mice. Most importantly, 16 showed memory-enhancing properties and it ameliorated memory deficits induced by scopolamine. The molecule outperformed most important comparators in selected tests, indicating its potential in the treatment of both cognitive and noncognitive (behavioral and psychological) symptoms of dementia.
如今，痴呆症的行为和心理症状（BPSD）最棘手的方面通过抗抑郁药、抗焦虑药和抗精神病药来解决，这些药物通常是超说明书用药。考虑到它们对痴呆症患者疗效有限，不良事件和认知衰退风险增加，对耐受性良好且有效的BPSD治疗仍存在未满足的需求。我们设计并合成了多功能配体，其在体外被表征为多巴胺受体（DR）的高亲和力部分激动剂、5-羟色胺受体（5-HTR）的拮抗剂和5-羟色胺转运体（SERT）的阻滞剂。此外，这些分子激活5-HTR并阻断5-HTR，同时对脱靶的盐皮质激素受体（MR）和人醚 - 去极化相关基因（hERG）通道没有相关亲和力。化合物16（N-{2-[4-(5-氯-1H-吲哚-3-基)-1,2,3,6-四氢吡啶-1-基]乙基}-3-甲基苯-1-磺酰胺）表现出广泛的抗精神病样、抗抑郁样和抗焦虑样活性，在小鼠中未引发运动障碍。最重要的是，化合物16显示出记忆增强特性，并改善了东莨菪碱诱导的记忆缺陷。在选定的测试中，该分子优于最重要的对照物，表明其在治疗痴呆症的认知和非认知（行为和心理）症状方面的潜力。
