Preclinical evaluation of AVN-322, novel and highly selective 5-HT6 receptor antagonist, for the treatment of Alzheimer’s disease

In recent years, 5-hydroxytryptamine subtype 6 receptor (5-HT6 receptor, 5-HT6R) has rapidly emerged as a promising therapeutic target for the treatment of neuropathological disorders, including Alzheimer’s disease (AD). Evidence indicates that 5-HT6 receptors are deeply implicated in the processes of learning and memory, while 5-HT6R antagonists were shown to improve cognition in animal models of cognitive impairment. Moreover, several selective 5-HT6R ligands are currently undergoing clinical trials against AD. Herein, we present the preclinical development of AVN-322, novel and highly selective 5-HT6R antagonist, for the treatment of AD. While having nanomolar binding affinity, the lead compound demonstrated the best selectivity index as compared to reference drug candidates. During the pharmacokinetic studies, AVN-322 showed high oral bioavailability and favorable blood-brain barrier (BBB) permeability. In vivo testing revealed its clear cognition enhancing effect without anxiolytic properties that are often associated with serotonin receptor antagonists. AVN-322 significantly restored both scopolamine- and MK-801-induced cognitive dysfunction. Taking into account its good safety profile and favorable pharmacokinetics, AVN-322 can be reasonably regarded as novel drug candidate for the treatment of neurological disorders.

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