Development of Gpr151 Modulators for the Treatment of Opioid Dependence

National Center For Advancing Translational Sciences

Investigators

Abstract

GPR151 is an orphan G-protein coupled receptor (GPCR) that is expressed in the central nervous system and immune system as well. It is also expressed in the medial habenula. Dr. Kenny and his team have found that Gpr151 co-localizes with mu opioid receptors in the medial habenula, and this orphan receptor regulates the inhibitory effects of opioids on habenular neurons. Moreover, they have found that Gpr151 plays a critical role in regulating the motivational properties of opioid drugs, such as morphine and oxycodone, in mice. This collaboration seeks to develop novel GPR151 modulators to facilitate long-term abstinence in opioid-dependent individuals. In collaboration with NCATS, this project has already identified first-in-class GPR151 modulators and accelerated further understanding of GPR151. This year, the team developed new assays to support chemistry efforts for the project, including a high-throughput internalization assay and a high-throughput split-luc CETSA. (Previously, the team developed primary, counter, orthogonal, and electrophysiology assays for this project.) Promising chemotypes were confirmed in the team’s beta-arrestin assay. Structural modeling to predict the binding model for lead optimization was also conducted. With multiple stages of HTS complete (over 76,000 compounds screened), and six promising drug-like chemical series identified, a robust medicinal chemistry campaign is in progress. To date, the team has completed eight rounds of SAR exploration; NCATS and their collaborator’s chemist have synthesized more than 300 unique analogs from a tricyclic ketone and a triazine chemical series. Medicinal chemistry efforts on the tricyclic ketone series already produced analogs with potent inverse agonism (EC50 < 100 nM) in the GPR151 beta arrestin assay. Drug metabolism and pharmacokinetics (DMPK) properties are being evaluated to check for CNS exposure to select promising candidates for validation in the collaborator’s animal addiction model. Furthermore, the team has screened over 150,000 natural products from the NCI Natural Products Library and has conducted confirmation testing. Although no significant hits were found, the next release of this library will also be screened. The collaborator is currently working on a manuscript that will include data from this project