Glycine transporters (GlyTs) are the Na+/Cl-dependent plasmalemmal neurotransmitter transporters. GlyTs comprise GlyT1 and GlyT2. They serve to terminate the signaling of glycine by mediating its reuptake from the synaptic cleft back into the presynaptic neurons. Glycine is a classical inhibitory neurotransmitter that hyperpolarizes the postsynaptic membrane through the activation of glycine receptors, which have an integral anion channel. Glycine also modulates the activity of excitatory NMDA-selective glutamate receptors at excitatory synapses by acting as a co-agonist. GlyT1 is abundant in the neocortex, thalamus and hippocampus, where it is expressed in astrocytes. GlyT1 takes part in glutamatergic neurotransmission as well. Meanwhile, GlyT2 exists in the brainstem, spinal cord and cerebellum, where it is responsible for glycine uptake into glycinergic and GABAergic terminals.

GlyTs are important targets for the research of central and peripheral nervous system disorders, including schizophrenia and related affective and cognitive disturbances, alcohol dependence, pain, epilepsy, breathing disorders and startle disease. Specifically, GlyT1 and GlyT2 play important roles by clearing synaptically released glycine or supplying glycine to glycinergic neurons to regulate glycinergic neurotransmission. Thus, inhibition of GlyTs can be used to modify pain signal transmission in the spinal cord.

SSR504734 is an orally active, selective and reversible GlyT1 inhibitor.

SSR504734 can inhibit human, rat, and mouse GlyT1. Importantly, SSR504734 blocks reversibly the ex vivo uptake of glycine, rapidly and for a long duration. In vivo, it can increase extracellular levels of glycine in the rat prefrontal cortex (PFC). Besides, SSR504734 prevents Ketamine-induced metabolic activation in mice limbic areas and reverses MK-801-induced hyperactivity, and increases EEG spectral energy in mice and rats, respectively. Finally, it increases extracellular dopamine in rat PFC. In conclusion, SSR504734 shows anti-schizophrenia, anti-anxiety, and anti-depression activities.

All in all, SSR504734 is a selective and reversible inhibitor of human, rat, and mouse GlyT1.

Harvey RJ, et, al. Nat Rev Drug Discov. 2013 Nov;12(11):866-85.