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 nociceptinopioid 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 anopioid use disorder medication and has demonstrated analgesic properties and efficacy in reducing cocaine andalcohol consumption, reportedly through its efficacy at NOP receptors. As NOP receptor activation reducesreward induced by mu activation, new molecules with bifunctional mu/NOP activities were designed to developcompounds with reduced abuse liability and increased efficacy as potential treatment for substance use disorderas compared to buprenorphine. Among a family of structurally related mixed compounds, Phoenix PharmaLabshas licensed a series of compounds with bifunctional NOP/mu activity. Two ligands, PPL-138 and PPL-143, wereshown to have the highest NOP receptor affinity and potency, with PPL-143 showing the greatest efficacy forNOP. Like buprenorphine, the two compounds have high affinity and low efficacy at mu receptors and high affinityand antagonist activity at kappa receptors. NOP receptor agonists have previously been demonstrated to blockMETH 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 ofPPL-138 and PPL-143 as candidate medications for METH use disorder (MUD) and to choose a lead compoundfor further development. Specific Aim 1 will assess the efficacy of both compounds in reducing METH-takingbehavior and motivation for METH in animals exposed to long METH access, a procedure that closely reflectsthe compulsive nature of MUD. As relapse is a central feature of MUD, the two compounds will also be evaluatedfor their ability to reduce reinstatement of METH-seeking behavior. These experiments will be conducted both inmale and female rats. Specific Aim 2 will determine safety of PPL-138 and PPL-143 by evaluating theirreinforcing properties and possible tolerance development. Concurrently to the first two aims, Specific Aim 3will conduct preliminary pharmacokinetic and ADME studies on PPL-143, which will integrate the behavioralresults. Collectively, the experiments planned in the present proposal will determine whether increasing the NOPcomponent in the context of a mu/NOP co-activation has any advantages over buprenorphine in terms of efficacyand safety. These experiments will also inform on further development of the mixed ligands as potential MUDpharmacotherapies, choose a lead compound for further development, and provide an important contribution tothe literature of the NOP system and the METH addiction fields.
Public Health Relevance Statement: Project narrative
Currently, clinically used drug abuse medications exist for treatment of addiction to opiates, alcohol, and nicotine,
but not psychostimulants such as methamphetamine. Compelling evidence suggests that compounds that co-
activate mu and NOP opioid receptors reduce drug abuse behaviors. This proposal aims to establish whether
compounds that more effectively interact with the NOP component, developed by Phoenix PharmaLabs, can
serve as future methamphetamine addiction treatments.
Project Terms: <κ opiate><κ opioid><κ opioid receptors><κ-OR><κOR><μ opioid receptors><μ-OR><μOR><μ receptors><κ receptor>
