Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in people older than 60 years. The need for improved therapies is unmet. Serotonin 4 (5-HT4) receptor may play a role in memory and learning. Activation of 5-HT4 receptors has been reported to modulate acetylcholine release and reduce beta amyloid accumulation. It is postulated that activation of 5-HT4 receptors will offer improved clinical efficacy and/or tolerability relative to cholinesterase inhibitors. 5-HT4 receptor partial agonists may be of benefit for both the symptomatic and disease-modifying treatment for cognitive disorders associated with AD. Based on the literature precedence and scaffold hopping approaches we have designed synthesized and characterized a series of quinoline carboxamide compounds. The compounds were screened in the cell based reporter gene assay, an end point luminescence assay which measures the levels of cAMP inside cells upon activation or inhibition of the receptor, using the luciferase reporter. The pharmacokinetics and brain penetration was evaluated in rodents. The efficacy was evaluated in animal models of cognition like NORT. The effect on the modulation of soluble amyloid precursor protein-α (sAPP-α) was studied in rat cortex. The synthesized compounds were potent and selective 5-HT4 partial agonists with adequate plasma exposures and brain penetration in Wistar rats. It has reversed memory deficit in object recognition task and promotes non-amyloidogenic APP processing in rats. Design, synthesis and pharmacological profiling of novel amide derivatives in preclinical symptomatic and disease modifying cognition models will be presented.

Quinoline carboxamide as 5-HT4 receptor partial agonist: Design, synthesis and pharmacological characterization

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.