Skip to main content

Glycine Transporter Type-1 and its Inhibitors

Buy Article:

$55.00 plus tax (Refund Policy)

The ionotropic glutamate receptor NMDA is allosterically modulated by glycine, a coagonist, its presence is an absolute requirement for receptor activation. The transport of glycine in glutamatergic synapse is carried out by glycine transporter-1 (GlyT1), a Na+/Cl--dependent carrier molecule. The primary role of GlyT1 is to maintain glycine concentrations below saturation level at postsynaptic NMDA receptors. Several isoforms of GlyT1 (a-e) have been identified, which are expressed both in glial and neuronal cell membranes. GlyT1 operates bidirectionally: it decreases synaptic glycine concentration when operates in normal mode and releases glycine from glial cells as operates in a reverse mode. It is expected that non-transportable, non-competitive inhibitors of GlyT1 may have therapeutic value in CNS disorders characterized by hypofunctional NMDA receptor-mediated glutamatergic neurotransmission. Accordingly, GlyT1 inhibitors exhibited antipsychotic profile in a number of animal tests. The first promising in vitro and in vivo experiments with glycine itself, and its N-methyl analogue, sarcosine, had initiated the syntheses of potential GlyT1 inhibitors with more complex structures, in which, however, the glycine or sarcosine moiety had always been incorporated. Those attempts led to the development of two compounds, ALX-5407 and Org-24461 with high inhibitory potency; however, none of which is now considered as a drug candidate due, most probably, to safety and/or pharmacokinetic issues. More recently, several structurally new series of highly potent inhibitors with no aminomethylcarboxy group have also been discovered. Some of them might be expected to fulfill all requirements for clinical development. The new generation of GlyT1 inhibitors may represent a novel treatment of patients suffering from schizophrenia and/or other neuropathological conditions.
No References
No Citations
No Supplementary Data
No Article Media
No Metrics

Keywords: Glycine; NFPS; NMDA receptor; Org-24461; astroglia cell; glycine transporter inhibitors; glycine transporters; glycine uptake; sarcosine; schizophrenia

Document Type: Research Article

Affiliations: Division of Preclinical Research, EGIS Pharmaceuticals Ltd, 116 Bokenyfoldi ut, 1165 Budapest, Hungary.

Publication date: 2006-04-01

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
  • Access Key
  • Free content
  • Partial Free content
  • New content
  • Open access content
  • Partial Open access content
  • Subscribed content
  • Partial Subscribed content
  • Free trial content
Cookie Policy
Cookie Policy
Ingenta Connect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more