Novel 1H-Pyrrolo3,2-cquinoline Based 5-HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimers Disease.
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 Alzheimers disease. Herein, we report the design, synthesis, and characterization of a novel class of 5-HT6R antagonists that is based on the 1H-pyrrolo3,2-cquinoline 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-pyrrolo3,2-cquinoline (14) (Ki 3 nM and Kb 0.41 nM). Pharmacological characterization of the 5-HT6Rs 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 mgkg) 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 mgkg). Moreover, 14 produced, in a 3-fold higher dose (MED 10 mgkg), antidepressant-like effects that were similar to those produced by SB-742457 (MED 3 mgkg). Together, these data suggest that the 4-(pyrrolidine-3-yl-amino)-1H-pyrrolo3,2-cquinoline 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 depressionanxiety symptoms that are comorbidities of Alzheimers disease.