ALX 5407 hydrochloride

ALX 5407 is a potent and selective inhibitor of the hGlyT1 glycine transporter. It completely inhibited glycine transport in the GlyT1 cells with an IC50 value of 3 nM [1].

GlyT1 is a family of glycine transporters. Transporters terminate the actions of both glycine and glutamate. There are at least three splice variants in the GlyT1 family, called 1A, 1B, and 1C. GlyT1 is distributed widely throughout the CNS, and that distribution correlates better with the localization of N-methyl-D-aspartate (NMDA) receptors than with the strychnine-sensitive glycine receptor [1].

QT6-1C cells were treated with 50 nM ALX 5407, and then were washed four times with HBS. After washing, 90 ?l of HBS was added. The rate at which ALX 5407 dissociated from the GlyT1C transporter was then measured. A long half-time was found. This indicates the binding of ALX 5407 to the GlyT1C transporter is essentially irreversible [1].

Using microdialysis, it was found that in vivo in rat prefrontal cortex (PFC), administration of ALX 5407 at a dose of 10 mg/kg, p.o., resulted in an increase of 40% in PFC glycine levels measured 60 to 90 min after drug administration, whereas the lower dose at 1 mg/kg elicited a slight, nonsignificant elevation [1].

Reference:
[1].  Atkinson BN, Bell SC, De Vivo M, et al. ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol, 2001, 60(6):1414-20.

Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia.[Pubmed:15759151]

Psychopharmacology (Berl). 2005 Apr;179(1):54-67.

RATIONALE: Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively. Research has implicated dysfunction of neurotransmission at the NMDA-type glutamate receptor in this disorder. OBJECTIVES: This study was conducted to examine whether compounds that enhance NMDA receptor (NMDAR) activity via glycine B site, D-serine and ALX 5407 (glycine transporter type 1 inhibitor), alter PPI and LI in the presence or absence of an NMDAR antagonist, MK-801. METHODS: C57BL/6J mice were tested in a standard PPI paradigm with three prepulse intensities. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in mice that previously received 0 (non-preexposed) or 40 noise exposures (preexposed) followed by two or four noise-foot shock pairings. RESULTS: Clozapine (3 mg/kg) and D-serine (600 mg/kg), but not ALX 5407, facilitated PPI. MK-801 dose dependently reduced PPI. The PPI disruptive effect of MK-801 (1 mg/kg) could be reversed by clozapine and ALX 5407, but not by D-serine. All the compounds were able to potentiate LI under conditions that disrupted LI in controls. MK-801 induced abnormal persistence of LI at a dose of 0.15 mg/kg. Clozapine, D-serine, and ALX 5407 were equally able to reverse persistent LI induced by MK-801. CONCLUSIONS: D-Serine and ALX 5407 display similar effects to clozapine in PPI and LI mouse models, suggesting potential neuroleptic action. Moreover, the finding that agonists of NMDARs and clozapine can restore disrupted LI and disrupt persistent LI may point to a unique ability of the NMDA system to regulate negative and positive symptoms of schizophrenia.

ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter.[Pubmed:11723250]

Mol Pharmacol. 2001 Dec;60(6):1414-20.

High-affinity glycine transport in neurons and glial cells is a primary means of inactivating synaptic glycine. We have synthesized a potent selective inhibitor of glycine transporter 1 (GlyT1), and characterized its activity using a quail fibroblast cell line (QT6). The glycine transporters GlyT1A, GlyT1B, GlyT1C, and GlyT2 were stably expressed in QT6 cells. The transporters expressed in these cells exhibited appropriate characteristics as described previously for these genes: Na(+)/Cl(-) dependence, appropriate K(m) values for glycine uptake, and appropriate pharmacology, as defined in part by the ability of N-methyl glycine (sarcosine) to competitively inhibit glycine transport. Furthermore, the characteristics of the transporters in the cell lines recapitulate the characteristics of glycine transporters observed in tissue preparations. We developed a sarcosine derivative, (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (ALX 5407), and examined its activity against the cloned glycine transporters. ALX 5407 completely inhibited glycine transport in the GlyT1 cells, with an IC(50) value of 3 nM, but had little or no activity at the human GlyT2 transporter, at other binding sites for glycine, or at other neurotransmitter transporters. The inhibition of glycine transport was essentially irreversible. ALX 5407 represents a novel tool in the investigation of N-methyl-D-aspartate-receptor function. This class of drug may lead to novel therapies in the treatment of schizophrenia.