Superiority of the Triple-Acting 5-HT 6 R/5-HT 3 R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT 6 R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats.

Autor:	Grychowska K; Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland., López-Sánchez U; Univ. Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France., Vitalis M; Molecular Mechanisms in Neurodegenerative Dementia (MMDN) Laboratory, University of Montpellier, EPHE-PSL, INSERM U1198, 34-095 Montpellier, France., Canet G; Faculty of Medicine, Laval University, CR-CHUQ, G1 V 4G2 Québec City (QC), Canada., Satała G; Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-324 Kraków, Poland., Olejarz-Maciej A; Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland., Gołębiowska J; Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-324 Kraków, Poland., Kurczab R; Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-324 Kraków, Poland., Pietruś W; Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-324 Kraków, Poland., Kubacka M; Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland., Moreau C; Univ. Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France., Walczak M; Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland., Blicharz-Futera K; Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland., Bento O; IBMM, Université de Montpellier, CNRS, ENSCM, 34-293 Montpellier, France.; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34-094 Montpellier, France., Bantreil X; IBMM, Université de Montpellier, CNRS, ENSCM, 34-293 Montpellier, France., Subra G; IBMM, Université de Montpellier, CNRS, ENSCM, 34-293 Montpellier, France., Bojarski AJ; Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-324 Kraków, Poland., Lamaty F; IBMM, Université de Montpellier, CNRS, ENSCM, 34-293 Montpellier, France., Becamel C; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34-094 Montpellier, France., Zussy C; Molecular Mechanisms in Neurodegenerative Dementia (MMDN) Laboratory, University of Montpellier, EPHE-PSL, INSERM U1198, 34-095 Montpellier, France., Chaumont-Dubel S; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34-094 Montpellier, France., Popik P; Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-324 Kraków, Poland., Nury H; Univ. Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France., Marin P; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34-094 Montpellier, France., Givalois L; Molecular Mechanisms in Neurodegenerative Dementia (MMDN) Laboratory, University of Montpellier, EPHE-PSL, INSERM U1198, 34-095 Montpellier, France.; Faculty of Medicine, Laval University, CR-CHUQ, G1 V 4G2 Québec City (QC), Canada.; CNRS, 75-016 Paris, France., Zajdel P; Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Nov 09; Vol. 66 (21), pp. 14928-14947. Date of Electronic Publication: 2023 Oct 05.
DOI:	10.1021/acs.jmedchem.3c01482
Abstrakt:	The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT 6 R antagonism and interaction with 5-HT 3 R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT 6 R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. PZ-1922 , but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HT 6 R/5-HT 3 R/MAO-B in AD.
Databáze:	MEDLINE
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