Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties
Language English Country France Media print-electronic
Document type Journal Article
PubMed
29291439
DOI
10.1016/j.ejmech.2017.12.053
PII: S0223-5234(17)31084-X
Knihovny.cz E-resources
- Keywords
- 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 Cells MeSH
- Imidazoles chemical synthesis chemistry pharmacology MeSH
- Cognition drug effects MeSH
- Rats MeSH
- Humans MeSH
- Molecular Structure MeSH
- Rats, Sprague-Dawley MeSH
- Rats, Wistar MeSH
- Pyridines chemical synthesis chemistry pharmacology MeSH
- Receptors, Serotonin metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- imidazo(4,5-b)pyridine MeSH Browser
- Imidazoles MeSH
- Pyridines MeSH
- Receptors, Serotonin MeSH
- serotonin 6 receptor MeSH Browser
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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