Novel 1H-Pyrrolo[3,2-c]quinoline Based 5-HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer’s Disease

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• 作者：Katarzyna Grychowska ; Grzegorz Satała ; Tomasz Kos ; Anna Partyka ; Evelina Colacino ; Severine Chaumont-Dubel ; Xavier Bantreil ; Anna Wesołowska ; Maciej Pawłowski ; Jean Martinez ; Philippe Marin ; Gilles Subra ; Andrzej J. Bojarski ; Frédéric Lamaty ; Piotr Popik ; Paweł Zajdel
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：July 20, 2016
• 年：2016
• 卷：7
• 期：7
• 页码：972-983
• 全文大小：527K
• 年卷期：0
• ISSN：1948-7193

文摘

Modulators of the serotonin 5-HT₆ receptor (5-HT₆R) offer a promising strategy for the treatment of the cognitive deficits that are associated with dementia and Alzheimer’s disease. Herein, we report the design, synthesis, and characterization of a novel class of 5-HT₆R antagonists that is based on the 1H-pyrrolo[3,2-c]quinoline core. The most active compounds exhibited comparable binding affinity to the reference compound, SB-742457, and markedly improved selectivity. Lead optimization led to the identification of (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (14) (K_i = 3 nM and K_b = 0.41 nM). Pharmacological characterization of the 5-HT₆R’s constitutive activity at Gs signaling revealed that 14 behaved as a neutral antagonist, while SB-742457 was classified as an inverse agonist. Both compounds 14 and SB-742457 reversed phencyclidine-induced memory deficits and displayed distinct procognitive properties in cognitively unimpaired animals (3 mg/kg) in NOR tasks. Compounds 14 and SB-742457 were also active in the Vogel test, yet the anxiolytic effect of 14 was 2-fold higher (MED = 3 mg/kg). Moreover, 14 produced, in a 3-fold higher dose (MED = 10 mg/kg), antidepressant-like effects that were similar to those produced by SB-742457 (MED = 3 mg/kg). Together, these data suggest that the 4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline scaffold is an attractive molecular framework for the development of procognitive agents. The results are promising enough to warrant further detailed mechanistic studies on the therapeutic potential of 5-HT₆R antagonists and inverse agonists for the treatment of cognitive decline and depression/anxiety symptoms that are comorbidities of Alzheimer’s disease.