Background: Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites
other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)-
pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of Prolyl-Leucyl-Glycinamide, is a
potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of
schizophrenia and extrapyramidal dysfunction.
Objective: In this study, we sought to examine the biomolecular underpinnings of PAOPA‘s therapeutic outcomes in preclinical models of schizophrenia.
Method: Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2
receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin-3), and phosphorylated mitogenactivated protein kinase (MAPKs), namely, extracellular signal-regulated kinases (ERK1/2) in the hippocampus, medial
pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification.
Results: Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor
expression in the dorsal striatum. These findings potentially underscore PAOPA’s therapeutic mechanism of action for the
positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in
the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggestive of a role for PAOPA in
treating cognitive and/or affective dysfunction in pre-clinical models.
Conclusion: While further studies are required to elucidate PAOPA’s mechanism of action, this study builds on prior
investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.