Bitopertin (developmental code names RG1678; RO-4917838) is a glycine reuptake inhibitor which was under development by

Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Switzerland, Swiss multinational corporation, multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, ...

as an adjunct to

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

s for the treatment of persistent

negative symptoms Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

or suboptimally controlled

positive symptoms Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

associated with

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. Research into this indication has been largely halted as a result of disappointing trial results. As of 2024, it is under development for the management of

erythropoietic protoporphyria Erythropoietic protoporphyria (or commonly called EPP) is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the ...

. Bitopertin is a glycine transporter 1 (GlyT1) inhibitor that increases levels of the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

by inhibiting its

reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmi ...

from the

synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in neuromuscular junction, muscles or glands. Chemical synapses allow neurons to form biological neural ...

. Glycine acts as a required co-agonist along with

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

at ''N''-methyl-D-aspartate (NMDA)

receptors Receptor may refer to: *Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...

Erythropoietic protoporphyria

Glycine is an early and crucial substrate in the biosynthesis of haem; inhibiting its transport by blocking GlyT1 reduces its availability for haem biosynthesis and this reduces the downstream accumulation of protoporphyrin IX in people with EPP.

Schizophrenia

Dysfunction of NMDA receptors may play a key role in the pathogenesis of schizophrenia and modulation of

glutamatergic Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonist ...

signalling via increased concentrations of glycine in the synaptic cleft may help potentiate NMDA receptor function and improve the symptoms of schizophrenia."Bitopertin for schizophrenia"
, "EuroScan", 14 August 2012 In a phase II proof-of-concept study, patients on bitopertin experienced a significant improvement in the change of the Negative Symptom Factor Score from baseline within 8 weeks (from −4.86 in the placebo group to −6.65 in the treatment group, p<0.05, per-protocol population). In addition, 83% of patients on bitopertin described an improvement of negative symptoms on the CGI-I1 versus 66% on placebo (p<0.05, per-protocol population).Glycine Transporter Type 1 (GLYT1) Inhibitor RG1678: Positive Results of the Proof-of-Concept Study for the Treatment of Negative Symptoms in Schizophrenia, Umbricht D. et al., ACNP 2010 In January 2014, Roche reported that bitopertin failed to meet its endpoints in two phase III trials assessing its efficacy in reducing negative symptoms of schizophrenia. Subsequently, in April 2014, Roche announced that it was discontinuing all except one of its phase III trials of bitopertin for schizophrenia.

References

{{Glycine receptor modulators Experimental drugs developed for schizophrenia Glycine reuptake inhibitors N-benzoylpiperazines Trifluoromethyl compounds Benzosulfones Organofluorides

Erythropoietic protoporphyria

Schizophrenia

See also

References