Identification of Mixed NOP/mu partial agonists as lead compounds for treatment ofmethamphetamine use disorder

Abstract Currently, clinically used drug abuse medications exist for treatment of addiction to opiates, alcohol, and nicotine, but not psychostimulants, such as methamphetamine (METH). Compounds that co-activate both nociceptin opioid peptide (NOP) and mu receptors have potential for treatment of drug abuse. In particular, buprenorphine, a partial mu agonist/kappa antagonist, which also acts as a low affinity and partial agonist at NOP, is used as an opioid use disorder medication and has demonstrated analgesic properties and efficacy in reducing cocaine and alcohol consumption, reportedly through its efficacy at NOP receptors. As NOP receptor activation reduces reward induced by mu activation, new molecules with bifunctional mu/NOP activities were designed to develop compounds with reduced abuse liability and increased efficacy as potential treatment for substance use disorder as compared to buprenorphine. Among a family of structurally related mixed compounds, Phoenix PharmaLabs has licensed a series of compounds with bifunctional NOP/mu activity. Two ligands, PPL-138 and PPL-143, were shown to have the highest NOP receptor affinity and potency, with PPL-143 showing the greatest efficacy for NOP. Like buprenorphine, the two compounds have high affinity and low efficacy at mu receptors and high affinity and antagonist activity at kappa receptors. NOP receptor agonists have previously been demonstrated to block METH conditioned place preference. Recently, we found that PPL-138 successfully decreases METH self- administration in rats. In this application, we propose animal studies to examine the safety and the efficacy of PPL-138 and PPL-143 as candidate medications for METH use disorder (MUD) and to choose a lead compound for further development. Specific Aim 1 will assess the efficacy of both compounds in reducing METH-taking behavior and motivation for METH in animals exposed to long METH access, a procedure that closely reflects the compulsive nature of MUD. As relapse is a central feature of MUD, the two compounds will also be evaluated for their ability to reduce reinstatement of METH-seeking behavior. These experiments will be conducted both in male and female rats. Specific Aim 2 will determine safety of PPL-138 and PPL-143 by evaluating their reinforcing properties and possible tolerance development. Concurrently to the first two aims, Specific Aim 3 will conduct preliminary pharmacokinetic and ADME studies on PPL-143, which will integrate the behavioral results. Collectively, the experiments planned in the present proposal will determine whether increasing the NOP component in the context of a mu/NOP co-activation has any advantages over buprenorphine in terms of efficacy and safety. These experiments will also inform on further development of the mixed ligands as potential MUD pharmacotherapies, choose a lead compound for further development, and provide an important contribution to the literature of the NOP system and the METH addiction fields.