Nanomolar TLR4 Antagonist CIAC101 Derived from (+)-Naltrexone Blocks Microglial Activation and Methamphetamine Addiction

Neuroimmune activation via Toll-like receptor 4 (TLR4) contributes to the pathophysiology of substance use disorders. Although (+)-naltrexone can antagonize TLR4 without engaging classical opioid receptors, its modest potency limits translational potential. The dual-site optimization at C3 and N17 was performed and identified <b>CIAC101</b>, an isobutyl-substituted (+)-naltrexone derivative with nanomolar TLR4 antagonism, representing ∼6200-fold higher potency than (+)-naltrexone. <b>CIAC101</b> dose-dependently blocked lipopolysaccharides-induced NF-κB activation and reduced the expression of pro-inflammatory mediators in microglia BV-2 cells. <i>In vivo</i>, low-dose <b>CIAC101</b> (0.2 mg/kg) attenuated methamphetamine (METH)-induced behavioral sensitization and conditioned place preference without intrinsic rewarding effects. Mechanistically, <b>CIAC101</b> reduced microglial activation and inflammatory gene expression within addiction-relevant circuits, notably medial prefrontal cortex and ventral tegmental area. Together, these data nominate <b>CIAC101</b> as a potent, central nervous system (CNS)-penetrant TLR4 antagonist that couples robust antineuroinflammatory activity with efficacy against METH-evoked neurobehavioral adaptations, advancing a neuroimmune strategy for treating stimulant addiction.