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.