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

Abstract : 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-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT6 receptor partial inverse agonist in Gs signaling (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.
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https://hal.umontpellier.fr/hal-02073217
Contributeur : Cécile Nowak <>
Soumis le : mardi 19 mars 2019 - 16:32:56
Dernière modification le : mardi 28 mai 2019 - 14:12:02

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D. Vanda, M. Soural, V. Canale, Séverine Chaumont-Dubel, G. Satala, et al.. Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties. Eur J Med Chem, 2018, 144, pp.716-729. ⟨10.1016/j.ejmech.2017.12.053⟩. ⟨hal-02073217⟩

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