Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-Based Multifunctional Ligands with Antipsychotic-Like, Mood-Modulating, and Procognitive Activity,Journal of Medicinal Chemistry

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Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-Based Multifunctional Ligands with Antipsychotic-Like, Mood-Modulating, and Procognitive Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00839
Adam Bucki ₁ , Monika Marcinkowska ₁ , Joanna Śniecikowska ₁ , Krzysztof Więckowski ₁ , Maciej Pawłowski ₁ , Monika Głuch-Lutwin ₁ , Anna Gryboś ₁ , Agata Siwek ₁ , Karolina Pytka ₁ , Magdalena Jastrzębska-Więsek ₁ , Anna Partyka ₁ , Anna Wesołowska ₁ , Paweł Mierzejewski ₂ , Marcin Kołaczkowski _{1,

3}

Affiliation

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 D₂R, antagonists of 5-HT₆R, and blockers of SERT. Moreover, the molecules activated 5-HT_1AR and blocked 5-HT₇R while having no relevant affinity for off-target M₁R 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.

中文翻译：

新型的3-（1,2,3,6-四氢吡啶基-4-基）-1 H-吲哚基多功能配体，具有抗精神病样，调节情绪和具有认知活性

如今，痴呆症的行为和心理症状（BPSD）最麻烦的方面是通过抗抑郁药，抗焦虑药和抗精神病药进行治疗，这些药物通常是不加标签的。考虑到它们在痴呆症患者中的适度疗效，不良事件和认知下降的风险增加，因此对耐受良好且有效的BPSD治疗存在未满足的需求。我们设计和合成了多功能配体，其体外特征为D ₂ R的高亲和力部分激动剂，5-HT ₆ R的拮抗剂和SERT的阻滞剂。此外，这些分子活化了5-HT _1A R并阻断了5-HT ₇ R，同时对脱靶的M ₁ R和hERG通道没有相关的亲和力。化合物16（N- {2- [4-（5-氯-1 H-吲哚-3-基）-1,2,3,6-四氢吡啶-1-基]乙基} -3-甲基苯-1-磺酰胺）广泛的抗精神病药，抗抑郁药和抗焦虑药样活性，不会引起小鼠运动障碍。最重要的是，16个具有记忆增强特性，并减轻了东pol碱引起的记忆障碍。在选定的测试中，该分子的性能优于最重要的比较剂，表明该分子具有治疗痴呆症的认知和非认知（行为和心理）症状的潜力。

更新日期：2017-08-18

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