Public Release: 

AVN-322 is a safe orally bio-available potent and highly selective antagonist

This research article by Dr. Alexandre V. Ivachtchenko et al. has been published in Current Alzheimer Research, volume 14, issue 3, 2017

Bentham Science Publishers

5-hydroxytryptamine subtype 6 receptor (5-HT6R) has been extensively considered as a promising therapeutic target for the treatment of neuropathological disorders. 5-HT6R were hypothesized to be implicated in the processes of learning, memory retention, and cognition. Several selective 5-HT6R ligands are currently undergoing clinical trials for treatment of Alzheimer's disease and schizophrenia, SB-742457 and Lu-AE-58054.

When tested against 70 therapeutic targets including receptors, kinases, ion channels, and transporters, AVN-322 appeared to be highly selective with the only two targets interacting with it, 5-HT6and 5-HT2B receptors.the AVN-322 displayed exclusively high binding affinity to 5-HT6R (Ki=0.39 nM) and potency to block functional cell response to serotonin (Ki=2.85nM, IC50 = 29 nM). Potency of the AVN-322 to block αMe-5-HT response of 5-HT2B expressing cells was 200-fold lower (IC50=6.16μM).

AVN-322 very slowly metabolized (18% degradation by 120 min) in human S9 microsomal fraction and did not inhibit seven major CYP450 cytochromes; only 70%-80% of AVN-0322 was bound to plasma proteins; it had high CACO-2 permeability with no transport asymmetry. AVN-322 showed good oral bioavailability in Wistar rats, 16.4%, dogs, 18%, and monkeys, 47%, and an excellent brain/plasma ratios of 1.6 in mice and 0.4-0.6 in rats.

In vivo testing revealed clear cognition enhancing effect of the AVN=0322. It significantly restored both scopolamine-induced and MK-801-induced cognitive dysfunction and demonstrated antipsychotic potential. In preclinical toxicity studies, both acute and 14-day studies (mice), semi-chronic, 30-days, (monkeys), and chronic, 6-months, (rats and rabbits), AVN-0322 demonstrated reasonably a good safety profile. No undesirable side effects were observed in Phase I human trials with a single dose of 18 mg tested.

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For more information about the article, please visit http://benthamscience.com/journals/current-alzheimer-research/volume/14/issue/3/page/268/

Reference: Ivachtchenko, AV.; et al (2017). AVN-322 is a Safe Orally Bio-Available Potent and Highly Selective Antagonist of 5-HT6R with Demonstrated Ability to Improve Impaired Memory in Animal Models. Current Alzheimer Research., DOI: 10.2174/1567205013666161108105005

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