Preclinical Evaluation of Dual NOP/Mu Partial Agonists for Methamphetamine Use Disorder

Background/Objectives: Methamphetamine (meth) use disorder (MUD) continues to pose a significant public health challenge, and there are currently no FDA-approved pharmacological treatments available. Compounds that simultaneously activate nociceptin opioid peptide (NOP) and mu opioid receptors offer a promising therapeutic approach for substance use disorders, including psychostimulant addiction. Methods: We evaluated two mixed NOP/mu receptor agonists for their ability to reduce meth intake using a translational drug-versus-food choice self-administration paradigm in male and female Sprague-Dawley rats. In addition, both compounds were tested in female rats for their effects on cue- and priming-induced reinstatement of meth-seeking behavior, established preclinical models of relapse. Results: PPL-138 and PPL-143 are structurally related bifunctional NOP/mu partial agonists that exhibit greater efficacy at NOP than at mu receptors, with PPL-143 showing the highest NOP efficacy. In behavioral assays, both compounds significantly reduced meth self-administration in male rats and exhibited comparable potency in this effect. In female rats, however, PPL-143 was less effective than PPL-138 in reducing meth intake. In reinstatement models, PPL-138, but not PPL-143, attenuated prime-induced reinstatement of meth seeking, whereas both compounds produced comparable increases in meth seeking in the cue-induced reinstatement paradigm. Additional findings indicated that PPL-138 enhanced meth-induced locomotor activation. Conclusions: The findings support mixed mu/NOP partial agonists as a promising pharmacological strategy for treating MUD, while also indicating a potential for increased drug seeking under certain conditions. Notably, enhancing the NOP component does not appear to meaningfully improve either the safety profile or the anti-meth efficacy of these bifunctional ligands.