Ian Egle

Recent progress in the use of glycine transporter-1 inhibitors for the treatment of central and peripheral nervous system diseases

The recent discovery of glycine transporters in both the CNS and the periphery suggests that the glycine transporter may play a critical role in NMDA receptor function by modulating glycine availability at the NMDA receptor-modulatory glycine site. Hypofunction of the glutamate system, specifically the NMDA receptor, is hypothesised to underlie some of the symptoms of schizophrenia. Localisation of the glycine transporter-1 (GlyT-1) within the brain correlates with NMDA receptor expression patterns, suggesting that GlyT-1 may regulate glycine concentrations at NMDA synapses. Consequently, raising extracellular glycine by inhibiting its uptake via GlyT-1 antagonism could facilitate NMDA receptor activation and thus provide an effective pharmacotherapy for the treatment of some of the symptoms of schizophrenia. This hypothesis has led to the acceleration of research efforts directed towards finding more potent and selective GlyT-1 inhibitors. Over the last 10 years the discovery of glycine-based pharmacotherapeutic treatments for CNS diseases such as schizophrenia has received considerable attention. The NMDA receptor hypofunction model provides a testable hypothesis for pharmacological intervention in the treatment of schizophrenia. Advances have been made on several fronts, from the research and discovery of selective GlyT-1 inhibitors, to the elucidation of the mechanism and pathophysiology of CNS diseases. The number of scientific publications published and patents filed in recent years testifies to the importance of this field. In light of the barrage of recent reviews and publications on glycine transporter inhibitors [1-10], this article highlights and reviews research advances published in the patent literature between 1997 and November 2003. The article is supplemented with selected publications on the design, synthesis and development of novel GlyT-1 inhibitors, their use in the treatment of CNS diseases and studies aimed at understanding their mechanism and pathophysiology. The emphasis is on recent advances in the possible involvement of GlyT-1 agents in the treatment of some of the symptoms of schizophrenia. By no means has any attempt been made to exhaustively review the literature, but primary references, together with citations of the latest literature reviews, have been included in each section.

(R)-3-(N-Methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives as high affinity h5-HT1B/1D ligands

A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) have been prepared using parallel synthesis, and their structure-activity relationship studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.