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Knackstedt LA , Wu L , Rothstein J , Vidensky S , Gordon J , Ramanjulu M , Dunman P , Blass B , Childers W , Abou-Gharbia M
MC-100093, a novel β-lactam GLT-1 enhancer devoid of antimicrobial properties attenuates cocaine relapse in rats
J Pharmacol Exp Ther. 2021 aug;378(2) :51-59
PMID: 33986035 URL: https://www.ncbi.nlm.nih.gov/pubmed/33986035
AbstractCocaine use disorder (CUD) currently lacks FDA-approved treatments. In rodents, the glutamate transporter-1 (GLT-1) is downregulated in the nucleus accumbens following cocaine self-administration and increasing the expression and function of GLT-1 reduces the reinstatement of cocaine-seeking. The beta-lactam antibiotic ceftriaxone upregulates GLT-1 and attenuates cue- and cocaine-induced cocaine seeking without affecting motivation for natural rewards. While ceftriaxone shows promise for treating CUD, it possesses characteristics that limit successful translation from bench to bedside, including poor brain penetration, a lack of oral bioavailability and a risk of bacterial resistance when used chronically. Thus, we aimed to develop novel molecules that retained the GLT-1 enhancing effects of ceftriaxone but displayed superior drug-like properties. Here we describe a new monocyclic beta-lactam, MC-100093, as a potent up-regulator of GLT-1 that is orally bioavailable and devoid of antimicrobial properties. MC-100093 was synthesized and tested in vitro and in vivo to determine physiochemical, pharmacokinetic and pharmacodynamic properties. Next, adult male rats underwent cocaine self-administration and extinction training. During extinction training, rats received one of four doses of MC-100093 for 6-8 days prior to a single cue-primed reinstatement test. Separate cohorts of rats were used to assess nucleus accumbens GLT-1 expression and MC-100093 effects on sucrose self-administration. We found that 50 mg/kg MC-100093 attenuated cue-primed reinstatement of cocaine-seeking while upregulating GLT-1 expression in the nucleus accumbens core. This dose did not produce sedation, nor did it decrease sucrose consumption or body weight. Thus, MC-100093 represents a potential treatment to reduce cocaine relapse. Significance Statement Increasing GLT-1 activity reliably reduces drug-seeking across classes of drugs, however, existing GLT1-enhancers have side effects and lack oral bioavailability. To address this issue, novel GLT-1 enhancers were synthesized and the compound with the most favorable pharmacokinetic and pharmacodynamic properties, MC-100093, was selected for further testing. MC-100093 attenuated cued cocaine-seeking without reducing food-seeking or locomotion and upregulated GLT-1 expression in the nucleus accumbens.
Notes1521-0103 Knackstedt, Lori A Wu, Lizhen Rothstein, Jeffrey D Vidensky, Svetlana Gordon, John Ramanjulu, Mercy Dunman, Paul Blass, Benjamin Childers, Wayne Abou-Gharbia, Magid Journal Article United States J Pharmacol Exp Ther. 2021 May 13:JPET-AR-2021-000532. doi: 10.1124/jpet.121.000532.