Brain-penetrant GPR88 agonists as novel therapeutics for opioid abuse - SUMMARY Submitted in response to RFA-DA-22-031, this application describes a multidisciplinary effort to develop novel, brain-penetrant, small-molecule GPR88 agonists to attenuate addiction-relevant behavioral responses to opioid drugs and ameliorate withdrawal syndrome in opioid-dependent individuals. GPR88 is an orphan G-protein coupled receptor (GPCR) with concentrated expression in striatopallidal (indirect pathway) medium spiny neurons (MSNs) in the striatum. Recent observations in transgenic mice demonstrate that GPR88 exerts an inhibitory influence over opioid receptor signaling in the striatum. Building on this and other recent promising preclinical observations, we propose to leverage our expertise in neurobiological mechanisms of opioid use disorders and small-molecule drug discovery to formally validate GPR88 as a drug target for opioid use disorders (OUD) and establish a drug development path forward by discovering GPR88 agonist lead compounds. We will leverage an in vivo murine model of opioid dependence we have developed and Gpr88-/- mice along with available GPR88 pharmacological tools. Unfortunately, published GPR88 agonists have limitations that restrict their utility in vivo and prevent their development into therapeutics. To address this short coming we will develop novel, potent GPR88 agonists with properties optimized for the treatment of opioid dependence. We are well positioned to accomplish this task. We recently conducted a GPR88 high throughput screen (HTS), using an innovative pharmacochaperone assay format, and identified a novel chemical scaffold exemplified by SBI-‘2037 as a validated GPR88 agonist. In addition, we have already developed robust cell-based assays (and appropriate counter-screens) to reliably monitor GPR88 function and its impact on opioid receptors. Leveraging these assets, we will conduct a medicinal chemistry campaign to increase potency and selectivity of the SBI-‘2037 scaffold with a critical path consisting of cellular assays focused on their utility in OUD that includes early assessment of absorption, distribution, metabolism and excretion (ADME) and brain penetration properties. To increase the overall probability of success, we intend to conduct an additional GPR88 HTS screening campaign in search of one or more back up series. We have established a stringent set of criteria for GPR88 agonist leads, and only compounds that match this profile will be advanced into efficacy testing in the intravenous oxycodone self- administration procedure in wild-type and Gpr88 knockout mice. This multidisciplinary research plan capitalizes on the uniquely relevant scientific and drug discovery expertise of our team of committed investigators and is an initial step towards our ultimate goal of developing GPR88 agonists as novel therapeutics to facilitate abstinence in opioid-dependent individuals.
