The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia □ S

ABSTRACT Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder. However, because of compound-related side-effects and the need for dose titration, a conclusive evaluation of the drug's efficacy in patients with schizophrenia has not been possible. In this series of studies in the rat, we compared the efficacy of the two new molecules to prevent a cognitive deficit induced by the N-methyl-D-aspartic acid receptor antagonist phencyclidine (PCP) in the reversal-learning paradigm in the rat. We also explored the effects of the drugs to prevent brain activation and neurochemical effects of PCP. We found that, like lamotrigine, both GSK2 and GSK3 were able to prevent the deficit in reversal learning produced by PCP, thus confirming their potential in the treatment of cognitive symptoms of schizophrenia. However, higher doses than those required for anticonvulsant efficacy of the drugs were needed for activity in the reversal-learning model, suggesting a lower therapeutic window relative to mechanism-dependent central side effects for this indication

Discovery of 1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (GSK163090), a Potent, Selective, and Orally Active 5-HT(1A/B/D) Receptor Antagonist.

In an effort to identify selective drug like pan-antagonists of the 5-HT(1) autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT(1) antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT(1A), 5-HT(1B), and 5-HT(1D) receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic

A novel process driving Alzheimer's disease validated in a mouse model: Therapeutic potential

Abstract Introduction The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood. Methods Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts—AD and a transgenic mouse model—to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology. Results T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14‐immunoreactive plaques. NBP14 is a cyclized version of T14, which dose‐dependently displaces binding of its linear counterpart to alpha‐7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild‐types. Discussion These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential