Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F18%3A73590970" target="_blank" >RIV/61989592:15110/18:73590970 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/18:73590970

Výsledek na webu

<a href="http://dx.doi.org/10.1016/j.ejmech.2017.12.053" target="_blank" >http://dx.doi.org/10.1016/j.ejmech.2017.12.053</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2017.12.053" target="_blank" >10.1016/j.ejmech.2017.12.053</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties

Popis výsledku v původním jazyce

A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT6 receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzy1)-7-(piperazin-1-yl)-3H-imidazo[4,5-6]pyridine) as potent 5-HT6 receptor partial inverse agonist in G(s) signaling (K-i = 6 nM, IC50=17.6 nM). Compound 17 displayed high metabolic stability, favorable cytochrome P450 isoenzyme (2D6, 3A4) profile, did not affect PgP-protein binding, without evoking mutagenic effects. It was orally bioavailable and brain penetrant. In contrast to intepirdine (SB-742457), which prevented 5-HT6R elicited neurite growth and behaved as an inverse agonist of cyclin-dependent kinase 5 (Cdk5), compound 17 has no influence on neuronal differentiation. Compound 17 exerted significant pro-cognitive properties in novel object recognition (NOR) task in rats reversing both phencyclidine- and scopolamine-induced memory deficits (MED = 1 and 0.3 mg/kg, p.o, respectively). These effects were similar to those produced by intepirdine. Additionally, combination of inactive doses of compound 17 (0.1 mg/kg) and donepezil (0.3 mg/kg) produced synergistic effect to reverse scopolamine-induced memory deficits. Accordingly, investigating putative divergence between inverse agonists and neutral antagonists as cognitive enhancers in neurodegenerative and psychiatric disorders is certainly of utmost interest. (C) 2017 Elsevier Masson SAS. All rights reserved.

Název v anglickém jazyce

Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties

Popis výsledku anglicky

A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT6 receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzy1)-7-(piperazin-1-yl)-3H-imidazo[4,5-6]pyridine) as potent 5-HT6 receptor partial inverse agonist in G(s) signaling (K-i = 6 nM, IC50=17.6 nM). Compound 17 displayed high metabolic stability, favorable cytochrome P450 isoenzyme (2D6, 3A4) profile, did not affect PgP-protein binding, without evoking mutagenic effects. It was orally bioavailable and brain penetrant. In contrast to intepirdine (SB-742457), which prevented 5-HT6R elicited neurite growth and behaved as an inverse agonist of cyclin-dependent kinase 5 (Cdk5), compound 17 has no influence on neuronal differentiation. Compound 17 exerted significant pro-cognitive properties in novel object recognition (NOR) task in rats reversing both phencyclidine- and scopolamine-induced memory deficits (MED = 1 and 0.3 mg/kg, p.o, respectively). These effects were similar to those produced by intepirdine. Additionally, combination of inactive doses of compound 17 (0.1 mg/kg) and donepezil (0.3 mg/kg) produced synergistic effect to reverse scopolamine-induced memory deficits. Accordingly, investigating putative divergence between inverse agonists and neutral antagonists as cognitive enhancers in neurodegenerative and psychiatric disorders is certainly of utmost interest. (C) 2017 Elsevier Masson SAS. All rights reserved.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ISSN

0223-5234

e-ISSN

—

Svazek periodika

144

Číslo periodika v rámci svazku

JAN 20 2018

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

14

Strana od-do

716-729

Kód UT WoS článku

000425198100054

EID výsledku v databázi Scopus

2-s2.0-85039724572