First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease.

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.

The preclinical discovery and development of cariprazine for the treatment of schizophrenia.

INTRODUCTION: Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult patients. It is typically administered orally once a day (a dose range 1.5 - 6 mg/day), does require titration, and may be given with or without food. It has a half-life of 2 - 4 days with an active metabolite that has a terminal half-life of 2 - 3 weeks. Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. This article is based on the available literature with respect to the preclinical and clinical findings and product labels of cariprazine. Expert opinion: Cariprazine shows highest affinity toward D3 receptors, followed by D2, 5-HT2B, and 5-HT1A receptors. It also shows moderate affinity toward σ1, 5-HT2A, and histamine H1 receptors. Long-term administration of cariprazine altered the abundance of dopamine, serotonin, and glutamate receptor subtypes in different brain regions. All these mechanisms of cariprazine may contribute toward its unique preclinical profile and its clinically observed benefits in the treatment of schizophrenia, bipolar mania, and possibly other psychiatric disorders.

Medium supplementation with zinc enables detection of imipramine-induced adaptation in glycine/NMDA receptors labeled with [3H]L-689,560.

Antidepressant drugs after chronic administration induce adaptive changes in the NMDA receptor complex. Radioligand-receptorbinding studies using [3H]5,7-dichlorokynurenic acid demonstrated a "down-regulation" of the glycine site/NMDA receptor following chronic treatment with antidepressants and electroconvulsive shock. However, binding procedure using this radioligand is time consuming because it requires the use of centrifugation method in the separation process. The introduction of a new radioligand of glycine/NMDA receptor, [3H]L-689,560 enables the application of a rapid filtration method. In the present study we demonstrate that 2-week treatment with imipramine (15 mg/kg ip) did not evoke alterations in specific [3H]L-689,560 binding and in IC50 value of glycine in displacing [3H]L-689,560 binding in the mouse or rat cortex. However, longer, a 4-week treatment with imipramine induced a significant 71% increase in IC50 value in displacing [3H]L-689.560 binding in the mouse cortex. Moreover, the presence of zinc in the incubation media, dose-dependently enhances detection of imipramine-induced increase in IC50 value of glycine in displacing [3H]L-689,560 binding in the rat cortex. The present data indicate that: (1) [3H]L-689,560 may be a suitable ligand for assessing adaptation of the glycine/NMDA sites and (2) the presence of zinc enhances detection of imipramine-induced reduction of glycine affinity for glycine/NMDA receptors labeled with [3H]L-689,560 which further indicates a significance of zinc in the mechanism of antidepressant treatment.