Tuesday, June 10, 2025
6/10/2025
Development of GPR139 antagonists for the treatment of pain - PROJECT SUMMARY Opioid analgesics are the most effective drugs to treat acute pain; however, chronic use leads to tolerance, dependance, and addiction. Misuse of prescription opioid drugs is the key reason for the current opioid epidemic in the US. The analgesic effects of opioids are primarily mediated through activation of the µ-opioid receptor (MOR), thus modulation of MOR signaling represents a promising strategy for pain management. GPR139 is extensively co-expressed with the MOR in the medial habenula and locus coeruleus, brain regions implicated in drug dependence and opioid analgesia. Multiple lines of evidence from cell-based and GPR139 knockout mice behavioral studies suggest that GPR139 negatively regulates MOR signaling and analgesic effects. Thus, we hypothesize that a GPR139 antagonist may enhance the analgesic efficacy of opioid medicines, thus necessitating a lower dose of opioids and thereby increasing opioid safety. Despite the premise of GPR139 as a novel target for the treatment of pain, investigation of GPR139 antagonism in behavioral responses to opioids (e.g., morphine) has been hampered by the lack of a suitable antagonist probe for in vivo studies. To date, our group has made significant progress in this regard. We have developed the GPR139 binding and functional assays to assess the ligand-receptor interaction and GPR139 activity. We have also carried out a preliminary structure-activity relationship (SAR) study of a known GPR139 antagonist scaffold, which led to the discovery of a promising lead JD-1 with improved potency, physicochemical properties, and metabolic stability. In this R21 application, we propose to develop a suitable antagonist probe and evaluate its effects in morphine analgesia through three iterative specific aims. In Aim 1, we will optimize potency, receptor selectivity, and drug-like properties of GPR139 antagonists using medicinal chemistry. In Aim 2, we will characterize compounds using a GPR139 calcium assay and a radioligand binding assay. Selected compounds will be assessed for receptor selectivity against GPR142, and further evaluated in a target profiling screen. Potent and selective compounds will then be characterized using a battery of ADME and pharmacokinetic assays. In Aim 3, we will test one best compound, developed in Aims 1 and 2, in thermal pain models (tail immersion and hot plate) and in morphine-induced conditioned place preference (CPP) to determine whether the GPR139 antagonist can facilitate morphine analgesia and at effective doses without producing the side effect on morphine reward. Overall, completion of this project will produce in vivo antagonist probes and provide the first direct evidence to validate the GPR139 antagonist as an adjuvant to morphine for the treatment of pain.
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