EXPLORING THE ANALGESIC EFFECTS OF DOPAMINE D3 RECEPTOR NEGATIVE ALLOSTERIC MODULATORS (D3R NAMS)

Pain management remains a critical aspect of healthcare, necessitating the constant search for novel analgesic targets and compounds. The dopamine D3 receptor has emerged as a potential player in modulating pain perception, making it an intriguing target for analgesic drug development. This study investigated the analgesic and behavioral effects of novel dopamine D3 receptor negative allosteric modulators (D3R NAMs), UNC6869, UNC8747, and UNC7108, in mice using the hot plate test and assessing locomotor activity. Male mice were administered 0, 40, and 80 mg/kg doses of these compounds using a cumulative dosing procedure. Hot plate assays were conducted to measure changes in responses to thermal stimuli (time to nocifensive behavior), and locomotor assays were performed to control for nonspecific behavioral effects. Results demonstrated a dose-dependent increase in the latency to nociceptive responses, suggesting potential analgesic effects mediated by UNC6869, UNC8747, and UNC7108. D3R NAMs did not significantly alter overall locomotor activity at analgesic doses, but potential toxicities were observed 24-48 hours later. Organ histopathology confirmed that 80 mg/kg exposure to these drugs produced acute kidney injury (AKI) along with some pathological changes in the spleen, liver, and pancreas. Overall, these studies explore the promising analgesic properties of D3R NAMs and highlight the importance of toxicology when testing a new class of compounds.