Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic,PAOPA: Examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia |
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| Affiliation: | 1. Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada;2. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada;3. Department of Medicinal Chemistry, University of Minnesota, Minneapolis, United States;1. Department of Biotechnological and Applied Clinical Sciences, University of L′Aquila, L′Aquila, Italy;2. Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States;3. Centre for Innovation in Neuropsychiatry, Institut de Recherches Servier, Croissy sur Seine, France;4. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy;1. CUNY Graduate Center, Neuropsychology Doctoral Program, United States;2. Queens College of the City University of New York, Department of Psychology, United States;3. Organic Chemistry Department, Southern Research Institute, United States;1. Department of Chemistry, Wuhan University, Wuhan 430072, China;2. College of Resource and Environmental Sciences, Wuhan University, Wuhan 430079, China;1. Biological and Chemical Research Centre, University of Warsaw, ul. Żwirki i Wigury 101, Warsaw 02-089, Poland;2. Faculty of Life Sciences, University of Bradford, Bradford, West Yorkshire, BD7 1DP, United Kingdom;3. Department of Neurology, University of Southern California, Los Angeles, CA 90089, United States;4. Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH B3 495 (Bâtiment CH) Station 6, Lausanne CH-1015, Switzerland |
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| Abstract: | Schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia. |
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