Dopamine is a major neurotransmitter in the central nervous system and among other functions is directly related to the rewarding effects of drugs of abuse. Dopamine signaling is mediated by D1, D2, D3, D4 and D5 receptors. The dopamine D3 receptor is a known target to treat a variety of neuropsychiatric disorders, including substance use disorders (e.g. cocaine and opioid), schizophrenia and depression. Despite extensive efforts, it has proven difficult to identify a lead molecule that selectively binds to D3 receptors (versus D2 receptors, for example), with the desired pharmacological and pharmacokinetic profile. For example, metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse.
The library of compounds of this technology is designed to have high affinity and specificity for the dopamine D3 receptor. Preliminary studies at NIDA indicate that selected lead compounds have promising in vivo activity in rodents, including reduced acquisition to self-administration of oxycodone, inhibition of reinstatement to oxycodone seeking, and ameliorating naloxone-precipitated withdrawal from oxycodone dependence, and that these lead compounds are metabolically stable.