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Novel non-sulfonamide 5-HT6receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties

D. Vanda, M. Soural, V. Canale, S. Chaumont-Dubel, G. Satała, T. Kos, P. Funk, V. Fülöpová, B. Lemrová, P. Koczurkiewicz, E. Pękala, AJ. Bojarski, P. Popik, P. Marin, P. Zajdel,

. 2018 ; 144 (-) : 716-729. [pub] 20171216

Jazyk angličtina Země Francie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc18010216

Grantová podpora
NV17-31834A MZ0 CEP - Centrální evidence projektů

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-HT6receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT6receptor partial inverse agonist in Gssignaling (Ki = 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.

Citace poskytuje Crossref.org

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