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Preclinical efficacy of the dual sigma receptor antagonist dopamine uptake inhibitor, CM699, as a medication for stimulant abuse (803.3)
Author(s) -
Katz Jonathan,
Hiranita Takato,
Lopez Jessica,
Brellenthin Angelique,
Mesangeau Christopher,
Alsharif Walid,
Kopajtic Theresa,
Coggiano Mark,
Jamalapuram Seshulatha,
Tsai ShangYi,
Avery Bonnie,
Su TsunPing,
Tanda Gianluigi,
McCurdy Christopher
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.803.3
Subject(s) - pharmacology , chemistry , stimulant , antagonism , sigma receptor , dopamine , antagonist , nucleus accumbens , agonist , dopamine transporter , receptor , medicine , biochemistry , dopaminergic
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 K 2 CO 3 in dimethylformamide (DMF), yielding a compound that was then coupled with 3 H ‐spiro[isobenzofuran‐1,4'‐piperidine] in the presence of K 2 CO 3 in DMF. The resulting compound, CM699, had affinities of 14, 2.30 and 318 nM at σ 1 Rs, σ 2 Rs and DAT, respectively. Antagonism at σ 1 Rs was confirmed by Western blots of σ 1 R‐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 T ½ = 4.4 hr). CM699 produced dose‐dependent insurmountable and selective antagonism of cocaine SA in rats (ED 50 = 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. Grant Funding Source : NIH Intramural Research Program