Journal
ACS CHEMICAL NEUROSCIENCE
Volume 7, Issue 7, Pages 972-983Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.6b00090
Keywords
5-HT6R antagonist; 5-HT6R inverse agonist; pyrrolo[3,2-c]quinoline; SB-742457; cognition; memory; novel object recognition test; forced swim test; Vogel test; Alzheimer's disease
Funding
- Polish Ministry of Science and Higher Education (MNiSW) [N N405 671540]
- European Union from the European Fund of Regional Development (EFRD)
- project Prokog [UDA-POIG.01.03.01-12-063/09-00]
- University Montpellier, CNRS
- Institut Carnot Chimie Balard
- Pale BioSante Rabelais
- French Embassy in Warsaw
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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-chlorophenypsulfonyl]-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.
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