As preclinical toxicity and efficacy both appear to

As preclinical toxicity and efficacy both appear to be associated with GlyT1 inhibition, it remains to be determined whether on-target toxicity can be separated from efficacy. The present study evaluated a series of GlyT1 inhibitors for target potency, mode of inhibition, residence time, activity in the DBA/2 mouse model of PPI [29], [30], and the presence of OP in a test of locomotor activity. d-Serine, an NMDA GlyB site agonist, and the weak but selective GlyT1 inhibitor sarcosine were included for comparison.
Materials and methods
Results
Discussion While the preclinical literature has clearly demonstrated that GlyT1 inhibition elevates extracellular glycine concentration, enhances NMDA receptor-dependent neurotransmission and improves cognition in animal models, identification of adverse effects associated with GlyT1 inhibition has raised concerns regarding safety and has hampered you can look here development [10], [28]. The intent of this study was to compare GlyT1 inhibitors that differed in chemotype, mode of inhibition, and target residence time and to evaluate the impact of the biochemical profile on ameliorating the obstinate progression associated with GlyT1 inhibition. ALX-5407 possessed off-target activities at the serotonin transporter, the neurokinin NK3 receptor, and the serotonin 5HT2A receptor, although these activities are relatively weak in comparison to the IC50 values for GlyT1 inhibition. It is not known from this type of profiling whether ALX-5407 acts as an antagonist or an agonist at these receptors, and it cannot be determined whether these activities affected PPI. Selective 5HT2A receptor antagonists [42], [43] and atypical antipsychotics that possess this activity [44], [45] have been reported to increase PPI [17], [29], [30]. Increased serotonin levels due to transporter inhibition as well as 5HT2A receptor agonists, on the other hand, decrease PPI [42], [43]. Antagonists of the neurokinin NK3 receptor have also been suggested as therapeutic targets for schizophrenia, although their activity in PPI has not been studied [46]. However, PPI was increased in DBA/2 mice by a variety of GlyT1 inhibitors [17], [19], [32], [41], including (S)-13h, Roche-7, and sarcosine that had no off-target activities. OP was a particularly unusual type of hyperactivity that was not only present after treatment with ALX-5407 but after treatment with other GlyT1 inhibitors [10] (data not shown). Of these other GlyT1 inhibitors, (S)-13h had no off-target activities, suggesting that OP was attributable to inhibition of GlyT1 and not to the off-target activities of ALX-5407. Consistent with the potential antipsychotic efficacy of NMDA receptor activation at the GlyB site, all four GlyT1 inhibitors and d-serine increased PPI in DBA/2 mice. Doses effective in increasing percent PPI for both the GlyT1 inhibitors and d-serine did not alter startle amplitude to the 120-dB pulses alone. Increases in PPI obtained herein were in agreement with previous reports for ALX-5407 and (S)-13h, in which ALX-5407 increased PPI at 1 and 10mg/kg and (S)-13h at 3, 30, and 100mg/kg [17], [32]. Additional GlyT1 inhibitors, SSR504734 and SSR103800, have also increased PPI in the DBA/2 mouse model [19], [41]. In other rodent models, ALX-5407 increased PPI at 1mg/kg in C57BL/6 mice treated with the NMDA antagonist MK-801 [37], and ORG 24598 (10mg/kg) reversed a PPI deficit induced by neonatal lesioning of the ventral hippocampus in rats [18]. GlyB site agonists have not previously been tested in DBA/2 mice but have increased PPI in other rodent models. d-Serine increased PPI in untreated C57BL/6 mice (600mg/kg [37]) and in ddY mice treated with MK-801 (1800 and 2700mg/kg [38], 300 and 900mg/kg [39]). Glycine increased PPI in the neonatal ventral hippocampal-lesioned rat model (800 and 1600mg/kg) and in ddY mice treated with MK-801 (800mg/kg) [18], [38]. Taken together, these data support the concept that augmentation of synaptic glycine levels increases PPI in a variety of models and may be anticipated to improve impairments involved in schizophrenia.