Preclinical Profile of CM699 as a Medication Candidate for Stimulant Use Disorder

Area of Science:

• Neuroscience
• Pharmacology
• Addiction Medicine

Background:

• Current treatments for stimulant-use disorder (SUD) lack proven efficacy.
• Sigma-receptor (σR) antagonists alone do not block stimulant reinforcement.
• Combined σR antagonism and dopamine transporter (DAT) blockade may attenuate stimulant self-administration.

Purpose of the Study:

• To investigate the efficacy of a dual DAT/σR inhibitor, CM699, for treating stimulant-use disorder.
• To assess CM699's pharmacological profile, in vivo effects, and abuse potential.

Main Methods:

• Synthesis and ex vivo characterization of CM699 for DAT and σR affinities.
• Assessment of CM699's effects on dopamine uptake and σR multimerization.
• In vivo studies in rats evaluating CM699's impact on cocaine-induced dopamine levels, self-administration, and its own abuse potential.

Main Results:

• CM699 demonstrated high affinity for DAT and σ₁Rs, inhibiting dopamine uptake ex vivo.
• CM699 effectively blocked cocaine self-administration and blunted cocaine's stimulatory effects in vivo.
• CM699 showed minimal abuse potential and blocked cocaine-induced conformational changes in DAT.

Conclusions:

• Dual DAT/σR inhibition represents a novel, preclinical approach for SUD medication development.
• CM699's mechanism involves modulating DAT conformation, offering a new therapeutic strategy.
• These findings provide proof of concept for developing dual-action medications for stimulant-use disorder.