Schizophrenia inhibitors

Since then, several potent and selective sarcosine-based inhibitors have been reported in the literature. Representative examples include 5 (LY2365109) [37,38], 6 ((R)-N[3-phenyl-3-(4 -(4-toluoyl)phenoxy)-propyl] sarcosine or (R)-NPTS) [39,40], 7 [41], 8 [42], 9 (JNJ-17305600) [43], and 10 [44]. Members of these series have demonstrated efficacy in several psychosis models [38,40] and JNJ-17305600 is reportedly in Phase I clinical trials for schizophrenia (data not available) [23]. 

SSR-504734 is a potent, selective, and reversible inhibitor (IC50 = 18 nM) that is competitive with glycine [47,51]. The inhibitor rapidly and reversibly blocked the uptake of [14C]glycine in mouse cortical homogenates, which was sustained for up to 7 h. Complete cessation of blockade and return to glycine basal levels occurred prior to 24 h, which is in stark contrast to NFPS (>24 h). SSR-504734 potentiated a nearly twofold increase of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices and produced an increase in contralateral rotations in mice when microinjected into the striatum. Microdialysis experiments indicated that the inhibitor induced a rapid and sustained increase in extracellular glycine levels in the PFC of freely moving rats [51]. The compound also demonstrated efficacy in a variety of psychosis models [51-53]. SSR-504734 was reportedly in clinical trials for schizophrenia but discontinued after Phase I (data not disclosed) [54]. 

Roche for their inhibitor RG1678. This trial provides compelling evidence that GlyT-1 inhibitors show promise as a novel class of antipsychotics that are effective at ameliorating the negative symptoms and cognitive dysfunction associated with schizophrenia. 

In this rapidly evolving field, the detection of PDE enzymes in the central nervous system (CNS) has stimulated interest in exploring potential applications of PDE inhibitors for treating CNS disorders such as Alzheimer s disease and other cognitive malfunctions, depression, anxiety, and schizophrenia. This review will focus on these therapeutic opportunities as well as new developments in the medicinal chemistry and biology associated with selected members of the PDE family, in particular PDEs 2, 4, 9, and 10. There have been a number of other reviews in this field in the past year that have covered selected individual PDE enzymes and potential pharmacologic applications of PDE inhibitors in CNS disorders [3,7,8]. 

A PDE10A inhibitor may also have the potential to treat the cognitive symptoms of schizophrenia. The principal evidence for this claim is papaverine reversal of a PCP-induced deficit in the EDID-set shifting assay in rats [35]. This assay translates into human behavior in the form of the Wisconsin Card Sorting Test (WCST). EDID-set shifting is a test of executive function, a measure in which schizophrenics have a robust deficit. It has also been shown recently that papaverine is efficacious in the Novel Object Recognition cognition assay [36]. 

Acetazolamide is a carbonic anhydrase inhibitor that reduces aqueous humour production and is therefore indicated in glaucoma to reduce the intraocular pressure. Salbutamol is a selective, short-acting beta2-agonist used as a bronchodilator in asthma. Tolbutamide is a short-acting sulphonylurea used in type 2 (non-insulin dependent) diabetes mellitus. Chlorpromazine is an aliphatic neuroleptic antipsychotic drug used in schizophrenia. Zafirlukast is a leukotriene-receptor antagonist that is indicated in the prophylaxis of asthma but should not be used to relieve acute severe asthma. 

Chlorpromazine is an aliphatic phenothiazine antipsychotic used in schizophrenia and which may exacerbate parkinsonism. Co-careldopa is a combination of levodopa and the peripheral dopa-decarboxylase inhibitor, carbidopa. Co-careldopa, amantadine, entacapone and bromocriptine are all indicated in the management of parkinsonism. 

Similar observations can be made with regard to the antidepressants introduced in the last 15 years or so. Both SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) represent some quantitative progress from the earlier antidepressants in that they are less toxic, cause fewer medically significant adverse events and support treatment compliance. As is the case for antipsychotics and schizophrenia, the development of these newer antidepressants was not based on fundamentally new insights into the pathophysiology of affective disorders. 

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