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Preclinical efficacy of the dual sigma receptor antagonist dopamine uptake inhibitor, CM699, as a medication for stimulant abuse (803.3)

Sigma receptor (σR) antagonists block many effects of stimulants, but not reinforcing effects assessed with self‐administration (SA). Yet, a recent study suggests that σR antagonism with dopamine transporter (DAT) inhibition selectively blocks stimulant SA. A compound with potential for dual σR‐DAT inhibition was synthesized by treating 1‐methyl‐2‐benzimidazolinone with 1,4‐dibromobutane in the presence of K2CO3 in dimethylformamide (DMF), yielding a compound that was then coupled with 3H‐spiro[isobenzofuran‐1,4'‐piperidine] in the presence of K2CO3 in DMF. The resulting compound, CM699, had affinities of 14, 2.30 and 318 nM at σ1Rs, σ2Rs and DAT, respectively. Antagonism at σ1Rs was confirmed by Western blots of σ1R‐EYFP bound to the ER chaperone, Binding immunoglobulin Protein (BiP). CM699 had no effect whereas the agonist, (+)‐pentazocine decreased BiP association. CM699 (5.0 mg/kg, iv) in rats produced a Cmax of 1.84 µg/mL in plasma, 5 min after injection which declined exponentially (overall T½ = 4.4 hr). CM699 produced dose‐dependent insurmountable and selective antagonism of cocaine SA in rats (ED50 = 3.99 mg/kg, ip) and blunted effects of cocaine on dopamine (DA) levels in the rat nucleus accumbens, indicating minimal abuse liability. The results provide preclinical proof of concept for dual σR/DAT inhibition as a novel approach for the development of medications to treat stimulant abuse.