Details

Autor(en) / Beteiligte

• Zagórska, Agnieszka
• Bucki, Adam
• Partyka, Anna
• Jastrzębska-Więsek, Magdalena
• Siwek, Agata
• Głuch-Lutwin, Monika
• Mordyl, Barbara
• Jaromin, Anna
• Walczak, Maria
• Wesołowska, Anna
• Kołaczkowski, Marcin

Titel

Design, synthesis, and behavioral evaluation of dual-acting compounds as phosphodiesterase type 10A (PDE10A) inhibitors and serotonin ligands targeting neuropsychiatric symptoms in dementia

Ist Teil von

• European journal of medicinal chemistry, 2022-04, Vol.233, p.114218-114218, Article 114218

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2022

Quelle

ScienceDirect

Beschreibungen/Notizen

• Neuropsychiatric symptoms (NPS), such as psychosis, depression and anxiety are frequently observed among patients with dementia. NPS is treated by off-label psychotropic medications that are only modestly effective in dementia patients, with a high risk of adverse events and cognitive decline. Considering the above, there is an unmet need for a well-tolerated and effective therapy of NPS in dementia. We designed and synthesized a library of dual-acting compounds as phosphodiesterase type-10A inhibitors and serotonin 5-HT1AR ligands. The most potent molecules, compounds 4 and 8, as partial agonists of 5-HT1AR and PDE10A inhibitors, exhibited a very high permeability of the blood-brain barrier. Compounds 4 and 8 displayed antipsychotic- and antidepressant-like activity and restored recognition memory deficits in mice. The overall effectiveness, pharmacokinetic and bioavailability studies imply the therapeutic-like potential of the presented dual-acting compounds as a method of treatment of NPS in dementia. [Display omitted] •Computer-aided design of 5-HT1A partial agonists/PDE10A inhibitors targeting NPS.•Synthesis, in vitro evaluation of a library of 6,7-dimethoxyquinazoline derivatives.•Dual-acting compounds displayed antipsychotic and antidepressant-like activity.•The most active compounds also restored recognition memory deficits in mice.•Lead compounds proved favorable bioavailability in PK studies.