COX-2/5-LOX inhibitors(University of Alberta)

Schizophrenia is a debilitating disorder affecting young adults displaying symptoms of cognitive impairment, anxiety, and early social isolation prior to episodes of auditory hallucinations. Cannabis use has been tied to schizophrenia-like symptoms, indicating that dysregulated endogenous cannabinoid signaling may be causally linked to schizophrenia. Previously, we reported that glutamatergic neuron-selective ablation of Lmo4, an endogenous inhibitor of the tyrosine phosphatase PTP1B, impairs endocannabinoid (eCB) production from the metabotropic glutamate receptor mGluR5. These Lmo4-deficient mice display anxiety-like behaviors that are alleviated by local shRNA knockdown or pharmacological inhibition of PTP1B that restores mGluR5-dependent eCB production in the amygdala. Here, we report that these Lmo4-deficient mice also display schizophrenia-like behaviors: impaired working memory assessed in the Y maze and defective sensory gating by prepulse inhibition of the acoustic startle response. Modulation of inhibitory inputs onto layer 2/3 pyramidal neurons of the prefrontal cortex relies on eCB signaling from the brain-derived neurotrophic factor receptor trkB, rather than mGluR5, and this mechanism was defective in Lmo4-deficient mice. Genetic ablation of PTP1B in the glutamatergic neurons lacking Lmo4 restored tyrosine phosphorylation of trkB, trkB-mediated eCB signaling, and ameliorated schizophrenia-like behaviors. Pharmacological inhibition of PTP1B with trodusquemine also restored trkB phosphorylation and improved schizophrenia-like behaviors by restoring eCB signaling, since the CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide blocked this effect. Thus, activation of PTP1B in pyramidal neurons contributes to schizophrenia-like behaviors in Lmo4-deficient mice and genetic or pharmacological intervention targeting PTP1B ameliorates schizophrenia-related deficits.

Structural and electronic factors influencing selective inhibition of cyclooxygenase-2 and 5-lipoxygenase (COX-2/5-LOX) were studied by using Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking, and Density Functional Theory (DFT) in a large set of molecules. The results of the ETM-NN calculations allowed for the selection of pharmacophoric molecular fragments, which could be taken as a basis for a system capable of predicting the COX-2/5-LOX inhibitory activity. For the more effective extraction of the pharmacophoric molecular fragments, docking of molecules into the active sites of the two enzymes was carried out to get data on the ligand-receptor interaction. To make an assessment of these interactions, stabilization energies were calculated by using Natural Bond Orbital (NBO) analysis. Docking and data on the electronic structures of active sites of enzymes helped to reveal effectively the peculiarities of the ligand-receptor binding. The system for the selective COX-2/5-LOX inhibitory activity prediction that has been developed as the result of the ETM-NN study recognized correctly 93% of compounds as highly active ones. Thus, this system can be successfully used for carrying out computer screening and synthesis of potent inhibitors of COX-2/5-LOX with diverse molecular skeletons.