A Preclinical Review on Novel μ Opioid Receptor Modulators as Potential Candidates for Opioid Use Disorder Treatment

OUD is a major worldwide health concern, with high rates of relapse and poor outcomes from existing treatments, including methadone, buprenorphine, and naltrexone. Recent preclinical research has revealed innovative immunotherapeutic and pharmacological approaches aimed at in-creasing safety and efficacy while reducing dependency and respiratory depression. The production of antibodies, anti-opioid immunotherapies, such as hapten-carrier-adjuvant conjugate vaccines block the penetration of opioids into the central nervous system and lessen their reinforcing effects without causing receptor-mediated toxicity. The Structure-based design and receptor modeling have developed remodeling of immunotherapy in the creation of novel μ-Opioid Receptor (MOR) modulators, including partial agonists and Positive Allosteric Modulators (PAMs). Novel modulators with varying efficacies at the MOR have shown promising therapeutic effects in several preclinical models (in vitro and in vivo) that are used to investigate abuse-related features. These novel modulators offer the benefits of MOR agonists, with fewer downsides than MOR agonists, partial agonists, and antagonists. G-protein biased signalling shows promise for separating analgesia from adverse effects like tolerance and dependence. Moreover, the Extended-release formulations and computational approaches have expedited the discovery of compounds with enhanced pharmacokinetic properties. This review shows how preclinical research on MOR modulators, particularly those with tunable intrinsic efficacy, may result in safer and more precisely focused treatments for opioid dependency while summarizing the available pharmacological choices for OUD. In order to better align experimental advancements with patient-centered therapeutic outcomes, future research should incorporate behavioral, molecular, and immunopharmacological approaches in addition to focusing on translational biomarkers, long-term safety profiling, sex-specific responses, and real-world effectiveness studies.