Glycine Transport Inhibitors

Conflict of Interest Dr. Javitt holds intellectual property rights for use of glycine, D-serine and glycine transport inhibitors in the treatment of schizophrenia. 

Schematic model of synaptic glycine regulation by glycine transport inhibitors...

Summary of negative symptom change across clinical trials in which W-methyl-D-aspartate (NMDA) full agonists (glycine, D-serine, D-alanine) or the glycine transport inhibitor sarcosine have been used in combination with antipsychotics other than clozapine (Originally published in Javitt (2008))... 

Javitt DC. 2008. Glycine transport inhibitors and the treatment of schizophrenia. Biol Psychiatry 63 6-8. 

Javitt DC, Balia A, Sershen H, Lajtha A. 1999a. A.E. Bennett Research Award. Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors. Biol Psychiatry 45 668-679. 

Javitt DC, Hashim A, Sershen H. 2005b. Modulation of striatal dopamine release by glycine transport inhibitors. Neuropsychopharmacology 30 649-656. 

Le Pen G, Kew J, Alberati D, Borroni E, Heitz MP, et al. 2003. Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats Reversal by glycine and a glycine transporter inhibitor. Biol Psychiatry 54 1162-1170. 

Javitt DC (2009) Glycine transport inhibitors for the treatment of schizophrenia symptom and disease modification. Curr Opin Drug Discov Dev 12 468-478... 

Scheme 37 Process for glycine transport inhibitor intermediate (Roche)...

Peptidomimetics typically function as antimicrobial compounds [15,17], but new functions are being discovered. WoHn et al. [18] found that p-amino acid derivatives act as glycine transport inhibitors, whereas Zhu et al. [19] have identified others that function as proteasome inhibitors. Armour et al. [20] incorporated them into... 

Boulay D, Pichat P, Dargazanli G, Estenne-Bouhtou G, Terra-nova JP, et al. 2008. Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia. Pharmacol Biochem Behav 91 47-58. 

Harsing LG Jr., Gacsalyi I, Szabo G, Schmidt E, Sziray N, et al. 2003. The glycine transporter-1 inhibitors NFPS and Org 24461 A pharmacological study. Pharmacol Biochem Behav 74 811-825. 

Kinney GG, Sur C, Burno M, Mallorga PJ, Williams JB, et al. 2003b. The glycine transporter type 1 inhibitor N-[3-(4 -fluorophenyl)-3-(4 -phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior. J Neurosci 23 7586-7591. 

Lindsley CW, Zhao Z, Leister WH, O Brien JA, Lemiare W, Williams DL Jr, Chen T-B, Chang RSL, Bumo M, Jacobson MA, Sur C, Kinney GG, Pettibone DJ, Tiller PR, Smith S, Tsou NN, Duggan ME, Conn PJ, Hartman GD. Design, synthesis and in vivo efficacy of novel glycine transporter-1 (GlyTl) inhibitors derived from a series of [4-Phenyl-l-(propylsulfonyl)piperidin-4-yl] methyl benzamides. ChemMedChem. 2006 1 807-811. 

---