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.

Abstract

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) (Ki = 3 nM and Kb = 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.

• Authors: 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
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 7 Issue 7 Pg. 972-83 (07 20 2016) ISSN: 1948-7193 [Electronic] United States
• PMID: 27100049 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1H-pyrrolo(3,2-h)quinoline
• 3-benzenesulfonyl-8-piperazin-1-ylquinoline
• Pyrroles
• Quinolines
• Receptors, Serotonin
• Serotonin Antagonists
• Sulfones
• Cyclic AMP
• Phencyclidine

Topics

• Alzheimer Disease (chemically induced, complications)
• Animals
• CHO Cells
• Cognition Disorders (drug therapy, etiology)
• Cricetulus
• Cyclic AMP (metabolism)
• Disease Models, Animal
• HEK293 Cells
• Humans
• Male
• Neuroblastoma (pathology)
• Phencyclidine (toxicity)
• Pyrroles (chemical synthesis, chemistry, therapeutic use)
• Quinolines (chemical synthesis, chemistry, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptors, Serotonin (biosynthesis, chemistry, metabolism)
• Serotonin Antagonists (chemistry, therapeutic use)
• Sulfones (chemistry, therapeutic use)