• 2018-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • While NR upregulation in the spinal cord is


    While NR1 upregulation in the spinal cord is known to contribute to pathological pain [7], [22] and furthermore, NR1 expression in the spinal cord has been shown to be reduced by continuous administration of the GlyT1-inhibitor ALX5407 [23], little is known about possible expressional changes of NR1 in DRG. Interestingly, selective knockout of NR1 in DRG was shown to lead to hyperexcitability in DRG neurons and hence to mechanical and thermal hypersensitivity [24], suggesting a complex and possibly antinociceptive effect of NMDA receptor activation in primary sensory neurons. In our study, however, expression of NR1 remained unchanged in DRG of neuropathic animals, while we did not investigate spinal NR-1 expression.
    NMDA receptor hypofunction is suggested to be involved in the pathophysiology of schizophrenia. The strongest evidence supporting this hypothesis is based on the observation that schizophrenic like symptoms can be induced in healthy subjects upon administration of NMDA blockers such as PCP. Thus, therapeutic intervention aimed at increasing NMDA synaptic tone is expected to show beneficial effect in schizophrenic patients. As glycine is an obligatory co-agonist at the NMDA receptor complex, one strategy to enhance NMDA receptor activity is to elevate extracellular levels of glycine in the local microenvironment of synaptic NMDA receptor. Glycine elevation can be achieved by inhibition of the glycine transporter 1 (GlyT1) which is co-expressed in the silymarin with the NMDA receptor and is responsible for glycine removal from the synaptic cleft., Strong support for this approach in the treatment of schizophrenia comes from clinical studies where glycine and -serine (co-agonists at the glycine site of NMDA receptor) and sarcosine (a prototypical weak GlyT1 inhibitor) improved positive, negative and cognitive symptoms in schizophrenic patients, when added to conventional therapy. As a result, considerable efforts have been focused on the development of selective GlyT1 inhibitors. The first examples reported were glycine or sarcosine derivatives. More recently, a wide variety of non amino-acid GlyT1 inhibitors have been disclosed.We also recently reported on synthesis and optimization of non-sarcosine based spiropiperidine compounds. During our effort to discover and develop structurally different and selective GlyT1 inhibitors, a high throughput screening of the Roche compound collection led to several hits containing 5-phenyl-1,3,4,5-tetrahydro-benzo [e] [1,4]–diazepine-2-ones linked to N-acylated glycine side-chains. The structurally simplest derivative already shows an IC of 154nM for inhibition of GlyT1. Compounds related to our high throughput screening hits have been described as tranquilizers, showing activities related to diazepam. Therefore, this potential liability of the benzodiazepine moiety as well as the rather high molecular weight of 506 prompted us to search for structurally simpler derivatives of these hits. During this optimization process it became rapidly apparent that the benzodiazepinone moiety was not essential for GlyT1 activity. This part of the molecule could be replaced by a diarylmethylamine moiety which nicely mimicked both aromatic rings of the benzodiazepinone moiety. These modifications led to a series of highly active GlyT1 inhibitors of the general formula (). We believe that the structure of these bis-amide derivatives is not related to other known mono-amide inhibitors which carry -sulfonylpiperidine moieties nor to the aminoacid class of GlyT1 inhibitors, (for example compounds of the type ) which all bear free silymarin carboxylic acid moieties. They might show some structural similarity to the benzyl amide SSR504734 which, however, contains a basic piperidine moiety and lacks the second amide bond (). Synthesis of the compounds described in this communication was performed by simple sequential amide coupling reactions (). Some of the required diarylmethylamines are commercially available; others were prepared by reaction of aryl-Grignard reagents on aromatic nitriles followed by sodium borohydride reduction of the intermediate imine. We also used the method of Laurent et al., involving acid catalyzed reaction of diarylmethanols with phenyl carbamate followed by cleavage of the intermediate with lithium hydroxide.