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 CIAC101, an
isobutyl-substituted (+)-naltrexone derivative with nanomolar TLR4
antagonism, representing ∼6200-fold higher potency than (+)-naltrexone. CIAC101 dose-dependently blocked lipopolysaccharides-induced
NF-κB activation and reduced the expression of pro-inflammatory
mediators in microglia BV-2 cells. In vivo, low-dose CIAC101 (0.2 mg/kg) attenuated methamphetamine (METH)–induced
behavioral sensitization and conditioned place preference without
intrinsic rewarding effects. Mechanistically, CIAC101 reduced microglial activation and inflammatory gene expression within
addiction-relevant circuits, notably medial prefrontal cortex and
ventral tegmental area. Together, these data nominate CIAC101 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.