Inhibitors of GlyT1 Affect Glycine Transport via Discrete Binding Sites

Abstract

In the forebrain, synaptic glycine concentrations are regulated through the glycine transporter GlyT1. Because glycine is a coagonist of the N-methyl-D-aspartate (NMDA) receptor (NMDAR), which has been implicated in schizophrenia, inhibition of GlyT1 is thought to provide an option for the treatment of schizophrenia.

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

“…It is important to note that these concerns are based on the effects of a subclass of GlyT1 inhibitors, which contain a sarcosine moiety in their structure. It has been shown that sarcosine-derived inhibitors exhibit an allosteric and irreversible inhibition, whereas nonsarcosine-derived structures were found to be reversible competitive inhibitors (Mezler et al, 2008). Consistent with an irreversible inhibition, sarcosine-derived inhibitors produce slowly increasing and sustained locomotor impairments (Perry et al, 2008), pointing to cumulating binding associated with a poorly controllable degree of inhibition.…”

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…GLYT1 and GLYT2 have several isoforms, thus increasing Gly transporter heterogeneity in the CNS (Aragón and López-Corcuera, 2003). However, because the isoforms exclusively involve changes in the intracellular N-and C-terminal domains, which have limited contribution to transporter function, it appears unlikely that differential targeting of individual isoforms by ligands will be possible; accordingly, all Gly transporter ligands examined across isoforms show identical pharmacological properties (Mezler et al, 2008).…”

“…Their identification has been driven by their potential use in the treatment of psychotic diseases and, besides being candidates for clinical studies, the ligands have excellent properties as pharmacological tools (Lechner, 2006; for review, see Dohi et al, 2009). The prototypic GLYT1-selective substrate Nmethyl glycine (sarcosine) has formed the basis for generations of highly potent and selective derivatives, including N- [3-(4Ј- (Bergeron et al, 1998;Atkinson et al, 2001;Aubrey and Vandenberg, 2001;Brown et al, 2001;Lowe et al, 2003;Mezler et al, 2008;Perry et al, 2008) (Table 5). For nonsarcosine GLYT1 inhibitors, several structurally diverse compounds have emerged from drug discovery programs, such as ((2-(4-benzo(1,3)dioxol-5-yl-2-tert-butylphenoxy) ethyl)methylamino)acetic acid (LY2365109) (Perry et al, 2008), 2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide (SSR504734) (Depoortère et al, 2005), SSR130800 (Boulay et al, 2008), N- [3-(4-chlorophenyl)-3-[4-(2-thiazolylcarbonyl)phenoxy]propyl]-N-methyl-glycine (CP-802,079) , and (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)-phenyl]-2-methyl-piperazin-1-yl-acetic acid (Lu AA20465) (Smith et al, 2004), in addition to a series of cyclic tetrapeptides that was recently isolated from a soil bacteria (Terui et al, 2008).…”

Synthesis and Biological Evaluation ofN-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1

“…In addition, competitive inhibition is potentially surmountable, which may circumvent potential mechanism-based adverse events due to excessive and prolonged glycine elevation. 43 Employing similar MichaelisMenten saturation binding experiments reported by Mezler and co-workers, 43 we assessed the mechanism of binding for (+)-67 at GlyT-1. A series of glycine transport experiments using a whole cell SPA assay with transfected HEK-293 cells expressing…”

“…It has been suggested that competitive GlyT-1 inhibitors might offer potential therapeutic advantages over non-competitive inhibitors as the degree of competitive inhibition could potentially depend on physiological glycine concentrations, whereas non-competitive inhibition would not. 43 Thus, competitive inhibitors may provide more impactful inhibition in areas of the CNS where physiological glycine concentrations are lower (i.e., forebrain). In addition, competitive inhibition is potentially surmountable, which may circumvent potential mechanism-based adverse events due to excessive and prolonged glycine elevation.…”