Identification of Non-competitive and Reversible Inhibitors of Glycine Transporter 2: A Promising Non-opioid...

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.