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 L-prolyl-L-leucyl-glycinamide, is a potent dopamine D2 receptor allosteric
modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and
Objective: In this study, we sought to examine the biomolecular underpinnings of PAOPA‘s therapeutic
outcomes in pre-clinical models of schizophrenia.
Methods: 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 mitogen-activated 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 the
therapeutic mechanism of action of PAOPA 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, suggesting a role of PAOPA in treating
cognitive and/or affective dysfunction in pre-clinical models.
Conclusion: While further studies are required to elucidate the mechanism of action of PAOPA,
this study discusses prior investigations and develops an early framework to describe the therapeutic
mechanism of action of PAOPA.