TY - JOUR
T1 - AVN-492, A Novel Highly Selective 5-HT6R Antagonist
T2 - Preclinical Evaluation
AU - Ivachtchenko, Alexandre V.
AU - Okun, Ilya
AU - Aladinskiy, Vladimir
AU - Ivanenkov, Yan
AU - Koryakova, Angela
AU - Karapetyan, Ruben
AU - Mitkin, Oleg
AU - Salimov, Ramiz
AU - Ivashchenko, Andrey
AU - Bezprozvanny, Ilya
N1 - Publisher Copyright:
© 2017 - IOS Press and the authors. All rights reserved.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - 5-HT receptor
KW - Alzheimer's disease
KW - antagonists
KW - anti-anxiety agents
KW - central nervous system agents
KW - memory enhancement
KW - obesity
KW - schizophrenia
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U2 - 10.3233/JAD-161262
DO - 10.3233/JAD-161262
M3 - Article
C2 - 28550249
AN - SCOPUS:85021266412
SN - 1387-2877
VL - 58
SP - 1043
EP - 1063
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 4
ER -