Further Development of Dual-Target Mu Opioid Receptor-Dopamine D3 Receptor (MOR-D3R) Ligands as Novel Therapeutics

Abstract Dual-target ligands that merge mu opioid receptor (MOR) partial agonists with dopamine D3 receptor (D3R) antagonists were designed, with the goal of discovering novel opioid analgesics. These compounds combine structural components of the MOR partial agonist TRV734 with a D3R scaffold (aryl-substituted trans-cyclopropylamine). (±)-LS02–14 exhibited higher affinity for MOR (Ki = 7.89 nM), compared to TRV734 (Ki = 54.7 nM) and (±)-LS01–64 (Ki = 85.2 nM), and lower D3R affinity (Ki = 952 nM) compared to (±)-LS01–64 (Ki = 361 nM), whereas TRV734 was inactive at D3R. Assays measuring Gi/o G-protein activation confirmed both eutomers, (R)-LS02–14 and (R)-LS01–64, as potent MOR partial agonists and D3R antagonists. Pharmacokinetic studies were followed by evaluation in the hot plate model of analgesia, in mice, which showed that TRV734 and (R)-LS02–14 produced robust antinociceptive effects. In addition, TRV734 (D3R/MOR = 1556) and (R)-LS02–14 (D3R/MOR = 75) exhibited similar abuse potential in heroin substitution tests, inhibited DA-dependent optical intracranial self-stimulation (oICSS), induced conditioned place preference and respiratory depression in mice. In contrast, (R)-LS01–64 (D3R/MOR = 6) produced modest antinociception and minimal effects on respiration. (R)-LS01–64 did not induce significant conditioned place preference nor did it maintain self-administration in more than 50% of mice in a heroin substitution test, while facilitating oICSS, at the highest dose tested. Together, these findings reveal a behavioral profile for (R)-LS01–64 characterized by acute enhancement of brain reward function but reduced reinforcing and conditioned rewarding effects compared with TRV734 and (R)-LS02–14. These findings support further optimization of dual-target MOR/D3R ligands as a promising strategy for developing opioid analgesics with improved therapeutic profiles.