AVN-492, A Novel Highly Selective 5-HT₆R Antagonist: Preclinical Evaluation

Article type: Research Article

Authors: Ivachtchenko, Alexandre V.^{a; b} | Okun, Ilya^{c; *} | Aladinskiy, Vladimir^e | Ivanenkov, Yan^{e; f} | Koryakova, Angela^d | Karapetyan, Ruben^d | Mitkin, Oleg^d | Salimov, Ramiz^g | Ivashchenko, Andrey^d

Affiliations: [a] Alla Chem LLC, Hallandale Beach, FL, USA | [b] Avineuro Pharmaceuticals, Inc., HallandaleBeach, FL, USA | [c] ChemDiv Inc (Retired), SanDiego, CA, USA | [d] Chemical Diversity Research Institute, Khimki, Moscow Region, Russian Federation | [e] Moscow Institute of Physics and Technology(State University), Dolgoprudny, Moscow Region, RussianFederation | [f] Department of Chemistry, Moscow State University, Moscow, Russian Federation | [g] Currently at Incuron LLC, Moscow, Russia

Correspondence: [*] Correspondence to: Ilya Okun, PhD, 5924 Seacrest View Road, San Diego, CA 92121, USA. Tel.: +1 858 775 6705; Fax: +1 858 630 3330; E-mail: ilyaokun@sbcglobal.net.

Abstract: Discovery of 5-HT6 receptor subtype and its exclusive localization within the central nervous system led to extensive investigations of its role in Alzheimer’s disease, schizophrenia, and obesity. In the present study, we present preclinical evaluation of a novel highly-potent and highly-selective 5-HT6R antagonist, AVN-492. The affinity of AVN-492 to bind to 5-HT6R (Ki = 91 pM) was more than three orders of magnitude higher than that to bind to the only other target, 5-HT2BR, (Ki = 170 nM). Thus, the compound displayed great 5-HT6R selectivity against all other serotonin receptor subtypes, and is extremely specific against any other receptors such as adrenergic, GABAergic, dopaminergic, histaminergic, etc. AVN-492 demonstrates good in vitro and in vivo ADME profile with high oral bioavailability and good brain permeability in rodents. In behavioral tests, AVN-492 shows anxiolytic effect in elevated plus-maze model, prevents an apomorphine-induced disruption of startle pre-pulse inhibition (the PPI model) and reverses a scopolamine- and MK-801-induced memory deficit in passive avoidance model. No anti-obesity effect of AVN-492 was found in a murine model. The data presented here strongly indicate that due to its high oral bioavailability, extremely high selectivity, and potency to block the 5-HT6 receptor, AVN-492 is a very promising tool for evaluating the role the 5-HT6 receptor might play in cognitive and neurodegenerative impairments. AVN-492 is an excellent drug candidate to be tested for treatment of such diseases, and is currently being tested in Phase I trials.

Keywords: 5-HT₆ receptor, Alzheimer’s disease, antagonists, anti-anxiety agents, central nervous system agents, memory enhancement, obesity, schizophrenia

DOI: 10.3233/JAD-161262

Journal: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1043-1063, 2017