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

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2013-04, Vol.42, p.89-96
• Main Authors: Tan, Mattea L., Basu, Dipannita, Kwiecien, Jacek M., Johnson, Rodney L., Mishra, Ram K.
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Administration, Oral; Allosteric; Animals; Antipsychotic; Antipsychotic Agents - pharmacokinetics; Antipsychotic Agents - pharmacology; Antipsychotic Agents - toxicity; Brain - drug effects; Brain - metabolism; D2 receptor; Drug Evaluation, Preclinical - methods; Humans; Male; Molecular Targeted Therapy - methods; MSH Release-Inhibiting Hormone - chemistry; Peptidomimetics - pharmacokinetics; Peptidomimetics - pharmacology; Peptidomimetics - toxicity; Pharmacokinetics; Pyrrolidinones - blood; Pyrrolidinones - pharmacokinetics; Pyrrolidinones - pharmacology; Pyrrolidinones - toxicity; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2 - drug effects; Schizophrenia; Schizophrenia - drug therapy; Tissue Distribution; Toxicology
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2013.02.004

► Study investigated allosteric peptide, PAOPA, specific for the dopamine D2 receptor. ► Study of PAOPA distribution showed it to effectively cross the blood–brain barrier. ► Pharmacokinetic profile of PAOPA was examined in rats across various time points. ► Toxic effects were examined through necropsy, histopathology, and blood analyses. ► Study showed robust drug safety, and thus platforms its progress to clinical trials. 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.