Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
29291439
DOI
10.1016/j.ejmech.2017.12.053
PII: S0223-5234(17)31084-X
Knihovny.cz E-zdroje
- Klíčová slova
- 5-HT(6) receptor inverse agonist, Cdk5 signaling, Dementia, Donepezil, Intepirdine, Neurodegenerative disorders, Novel-object recognition test, Phencyclidine, Pro-cognitive activity, Scopolamine, Solid-supported synthesis, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridines,
- MeSH
- HEK293 buňky MeSH
- imidazoly chemická syntéza chemie farmakologie MeSH
- kognice účinky léků MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- molekulární struktura MeSH
- potkani Sprague-Dawley MeSH
- potkani Wistar MeSH
- pyridiny chemická syntéza chemie farmakologie MeSH
- receptory serotoninové metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- imidazo(4,5-b)pyridine MeSH Prohlížeč
- imidazoly MeSH
- pyridiny MeSH
- receptory serotoninové MeSH
- serotonin 6 receptor MeSH Prohlížeč
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.
Citace poskytuje Crossref.org
