Identification of Non-competitive and Reversible Inhibitors of Glycine Transporter 2: A Promising Non-opioid Therapeutic Strategy for Neuropathic Pain

Glycine transporter
2 (GlyT2) regulates extracellular glycine in
the central nervous system (CNS) and is a promising target for restoring
inhibitory neurotransmission in chronic pain. Although GlyT2 inhibitors
show analgesic efficacy in rodent neuropathic pain models, the prototypical
inhibitor ORG25543 (1) is limited by poor pharmacological
properties, including slow dissociation kinetics and neuromotor toxicity
at therapeutic doses, recapitulating the phenotype of homozygous GlyT2
knockout (GlyT2–/–) mice.
To address these challenges, we developed a series of second-generation,
conformationally restricted indoline analogues that act as noncompetitive
and reversible GlyT2 inhibitors with varied potency and recovery kinetics.
Among them, RPI-GLYT2-82 produced effective analgesia in murine neuropathic
pain models without inducing excitatory neuromotor side effects observed
with ORG25543. Collectively, these findings underscore the translational
potential of reversible GlyT2 inhibitors as safe, nonopioid therapeutics
for the management of neuropathic pain and provide a foundation for
continued optimization of this chemotype toward preclinical candidate
selection.