Paper Title
PAOPA, A POTENTIAL NEW GENERATION OF ALLOSTERIC DRUG FOR THE TREATMENT OF CNS DISORDERS.

Abstract
Allosteric modulators (AMs) of G-Protein coupled receptors (GPCRs are emerging as a new class of orally available small molecules that may offer a competitive advantage over conventional neuroprotective agents. This potential stems from their key pharmacological features. AMs are highly selective for their target and act in the presence of natural and artificial agonists. Because of this, they have a self-limiting activity, and levels of endogenous ligands set the ceiling of their effect. Thus, AMs can be developed into a new class of drugs for the treatment of diseases that are superior to currently available drugs. we have synthesized and evaluated over 185 analogues of the endogenous brain peptide Pro-Leu-Glycinamide (PLG) for their pharmacological effects on dopamine (DA) receptors. Amongst them, PAOPA (3(R) –(2S) – pyrrolidinyl(carbonyl) amino-2oxo-1-pyrrolidine acetamide )was the most potent modulator of both D2S and D2L isoforms of DA D2R. Experiments were performed in several in vitro and in vivo preclinical models of schizophrenia and Parkinson’s disease . Direct radio receptor binding assays were carried by using tritium labeled DA receptor agonists and antagonists in human neuroblastoma cell lines and rat brain striatal membranes. Preclinical models of Schizophrenia were developed using amphetamine sensitization. Parkinson’s model was induced by unilateral injection of 6-hydroxydopamine in the substantia nigra. Both models displayed all the criteria of ideal preclinical models ,that is face validity, construct validity and predictive validity.Results show that It can increase agonist binding without affecting antagonist binding. We have compelling evidence to 1. Support PAOPA as a positive AMsof DA D2Rs, facilitating agonist (DA) binding to this receptor. 2. Demonstrate the specific interaction between PAOPA and DA D2R allosteric site. 3. Demonstrate that PAOPA can readily cross the blood-brain barrier to prevent and reverse behaviouralabnormalitiesin preclinical animal models of . 4. Indicate that PAOPA has no adverse or toxic effects in preclinical models .In conclusion , we have developed a promising new drug, PAOPA for the treatment of brain illnesses such as schizophrenia and Parkinson’s disease which displays high specificity and lack of adverse effects . The mechanism of action and preclinical efficacy of PAOPA has been thoroughly investigated. Additionally, this allosteric modulator of dopamine D2 receptors may also be of therapeutic value for other dopamine associated illnesses. The technology has US patent (PCT/CA2011000968).The work was funded by the National Science and Engineering Research Council of Canada 06510. Keywords - Allosteric Drugs, Dopamine Receptors, Parkinsons Disease, Schizophrenia.