Background: In recent years, 5-hydroxytryptamine subtype 6 receptor (5-HT6 receptor, 5-
HT6R) has emerged as a promising therapeutic target for the treatment of neuropathological disorders,
including Alzheimer’s disease (AD) and schizophrenia. 5-HT6 receptors were hypothesized to be implicated
in the processes of learning, memory, and cognition with 5-HT6R antagonists being effective in
animal models of cognition and memory impairment. Several selective 5-HT6R ligands are currently
undergoing clinical trials for treatment of AD.
Methods: We describe results of preclinical development of a novel and highly selective and potent 5-
HT6R antagonist, AVN-322, as a clinical candidate for the treatment of AD to improve concurrent debilitation
of memory and cognition in the AD patients, and schizophrenia as a substance with antipsychotic
effect. In the manuscript, we present its in vitro and vivo efficacy, ADME, pharmacokinetics in animals
and in humans, and toxicity.
Results: While having high binding affinity in medium picomolar range, the lead compound demonstrates
substantially better selectivity index then the reference drug candidates currently being tested in
clinical studies. AVN-322 showed high oral bioavailability and favorable blood-brain barrier (BBB)
penetration. In vivo testing revealed its clear cognition enhancing effect. AVN-322 significantly restored
both scopolamine- and MK-801-induced cognitive dysfunction and demonstrated antipsychotic potential.
Conclusion: Taking into account its good safety profile and favorable pharmacokinetics, AVN-322 can
be reasonably considered as a novel drug candidate for the treatment of neurological disorders such as
AD and/or schizophrenia.