Novel non-sulfonamide 5-HT 6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties

Eur J Med Chem. 2018 Jan 20;144:716-729. doi: 10.1016/j.ejmech.2017.12.053. Epub 2017 Dec 16.

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.

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 terms

  • Animals
  • Cognition / drug effects*
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Male
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Serotonin / metabolism*
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Pyridines
  • Receptors, Serotonin
  • imidazo(4,5-b)pyridine
  • serotonin 6 receptor