Glycine transporter (GlyT1) inhibitors with reduced residence time increase prepulse inhibition without inducing hyperlocomotion in DBA/2 mice

Biochemical Pharmacology
Karla KopecMichael J Marino

Abstract

Inhibition of the glycine transporter type 1 (GlyT1) leading to potentiation of the glycine site (GlyB) on the N-methyl-d-aspartate (NMDA) receptor has been proposed as a novel therapeutic approach for schizophrenia. However, sarcosine-based GlyT1 inhibitors produce undesirable side effects including compulsive walking and respiratory distress. The influence of specific biochemical properties of GlyT1 inhibitors, such as mode of inhibition and residence time, on adverse effects is unknown. Two GlyT1 inhibitors that contain a sarcosine moiety, sarcosine and ALX-5407, and two compounds that do not contain a sarcosine moiety, Roche-7 and Merck (S)-13h, were evaluated for their potency, mode of inhibition, and target residence times in vitro, and modulation of prepulse inhibition (PPI) and locomotor activity in vivo. (S)-13h and sarcosine were competitive inhibitors while ALX-5407 and Roche-7 demonstrated mixed noncompetitive inhibition. Potency of GlyT1 inhibition (ALX-5407>(S)-13h>Roche-7≫sarcosine) did not correlate with residence time on GlyT1 (sarcosine=Roche-7≪(S)-13h<ALX-5407). ALX-5407 and (S)-13h induced compulsive walking, termed obstinate progression (OP), at doses that increased PPI in DBA/2 mice, demonstrating that OP ...Continue Reading

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Oct 1, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Bita Moghaddam, Daniel Javitt
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