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

There currently are no medications proven to be effective for the treatment of stimulant-use disorder (SUD). Sigma-receptor (σR) antagonists block many effects of stimulant drugs but not the reinforcing effects assessed with self-administration in rats. However, a recent study suggests that σR antagonism combined with a dopamine (DA) transporter (DAT) blockade selectively attenuates stimulant self-administration. A compound with potential for dual DAT/σR inhibition, CM699, was synthesized and had the necessary ex vivo affinities of 311 and 14.1 nM at DAT and σ₁Rs, respectively. CM699 inhibited DA uptake ex vivo. Antagonist effects at σ₁Rs by CM699 were confirmed with a recently reported pharmacological assay: CM699 increased, whereas the σ₁R agonist, (+)-pentazocine, decreased σ₁R multimers detected in nondenaturing protein gels, and CM699 blocked the effects of (+)-pentazocine. CM699 after intravenous administration (5.0 mg/kg) in rats had an elimination half-life of 4.4 h. In rats, CM699 after intraperitoneal administration blunted the stimulatory effects of cocaine on DA levels in the nucleus accumbens and insurmountably blocked cocaine self-administration, indicating efficacy as a cocaine antagonist in vivo. When given alone, CM699 was not self-administered nor had significant effects on nucleus accumbens DA, suggesting minimal, if any, abuse potential. Further, in a biochemical assay designed to probe the conformation of DAT, (+)-pentazocine potentiated cocaine-induced cysteine accessibility of DAT transmembrane domain 6a, suggesting a shift in the conformational equilibrium of DAT toward outward-facing, whereas CM699 blocked this effect. The results provide preclinical proof of concept for dual DAT/σR inhibition as a novel DAT-conformational approach for the development of medications to treat SUD.

cocaine; dopamine transporter; self-administration; sigma1 receptor; stimulant use disorder.