Novel GLT-1 activators for the treatment of alcohol dependence: preclinical studies

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Abstract: Emerging evidence indicates that many aspects of ethanol (EtOH) and drug dependence involve changes in glutamate transmission in central reward brain regions, including the nucleus accumbens and medial prefrontal cortex. Upregulation of glutamate transporter 1 (GLT-1) in these brain regions with i.p. injections of several β-lactams, including ceftriaxone, attenuated EtOH intake and EtOH relapse behaviors in alcohol-preferring rats (P rats). GLT-1 is responsible for the uptake of the majority of extracellular glutamate. In addition, cystine/glutamate exchanger (xCT) is another astroglial protein involved in regulating glutamate homeostasis. The premise of this work is to pursue a very extensive preclinical study that will investigate the neuropharmacology of novel GLT- 1 upregulators, MC-100093, and derivatives as well as a non-antibiotic FDA-approved β-lactam, clavulanic acid (CLAV), which is a β-lactamase inhibitor in both continuous EtOH intake and EtOH relapse behavior. In this study, we will investigate novel -lactams (MC-100093 and derivatives), which do not have antibiotic action, on the expression of GLT-1 and xCT, and anti-inflammatory effects. The experimental goals are: (Aim 1) Investigate the pharmacokinetics.pharmacodynamics and target engagement of MC-100093 and, its derivatives and CLAV to determine dosing, and nominate efficacy biomarkers for subsequent use in P rats; (Aim 2) Investigate the pharmacological mechanisms of action of MC-100093 and its derivatives, and CLAV involving the upregulation of GLT-1 and xCT, and attenuation of neuroinflammation in P rats. Data generated from this project will show that novel drugs can upregulate GLT-1 expression and could have significant clinical implications for alcohol dependence and other neuropsychiatric disorders characterized by the hyperglutamatergic state as well as modulating neuroinflammation associated with an increase in extracellular glutamate in central brain regions that regulate drug dependence; and (Aim 3) to identify optimized, more lipophilic analogs of MC-100093 with drug-like properties and pharmacokinetic profiles that support once-dosing.