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.

Effects of Acute Consumption of Noni and Chokeberry Juices vs. Energy Drinks on Blood Pressure, Heart Rate, and Blood Glucose in Young Adults.

The purpose of this study has been to determine the effect of acute consumption of noni and chokeberry juices vs. energy drinks on blood pressure, heart rate, and blood glucose. The subjects divided into 4 groups, which consumed three portions of noni or chokeberry juices (30 mL or 200 mL, respectively) and energy drink (ED) or water (200 mL) at one-hour intervals. All participants had their blood pressure (BP), both systolic and diastolic BP (SBP and DBP), as well as heart rate (HR) and blood glucose (BG), measured. Consumption of noni juice caused a significant decrease in SBP and DBP of 5.0% and 7.5%, respectively, while, the consumption of chokeberry juice slightly decreased only DBP by 3.6%. On the contrary, consumption of three portions of EDs caused a significant increase in DBP by 14.7%. The BG of participants consuming noni juice decreased by 7.3%, while the consumption of EDs increased BG by as much as 15.8%. Acute consumption of noni juice contributed to a significantly decreased SBP, DBP, and HR as well as a mild reduction of BG. Consumption of chokeberry juice caused only a slight reduction of DBP. Contrary to juices, EDs consumption resulted in an increase of blood pressure (especially DBP) and blood glucose. The results of the study showed that noni juice may be effective in lowering blood pressure and blood sugar levels, but there is a need to continue research on the long-term effect of this juice.

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.

3-Aminomethyl Derivatives of 2-Phenylimidazo[1,2-a]-pyridine as Positive Allosteric Modulators of GABAA Receptor with Potential Antipsychotic Activity.

Schizophrenia is a mental illness characterized by behavioral changes as well as anatomical and neurochemical abnormalities. There has been remarkable progress in the drug discovery for schizophrenia; however, antipsychotics that act through molecular targets, other than monoaminergic receptors, have not been developed. One of the hypotheses of schizophrenia states that GABAergic dysfunction might be implemented in the pathophysiology of this disease. Our recent findings and previous clinical observations have suggested that modulation of GABAergic system through α1-GABAA receptors would represent an original approach for the treatment of schizophrenia. This study presents the synthesis and biological evaluation of a series of fluorinated 3-aminomethyl derivatives of 2-phenylimidazo[1,2-a]-pyridine as potential antipsychotic agents. Compound 7 has a high affinity for GABAA receptor (Ki = 27.2 nM), high in vitro metabolic stability, and antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 10 mg/kg). Compound 7 represents a promising point of entry in the course of development of antipsychotic agents with a nondopaminergic mechanism of action.

Vitamin D and vitamin D receptor activators in treatment of hypertension and cardiovascular disease.

Vitamin D plays an essential role in calcium homeostasis and bone metabolism, but recent research has exposed a larger spectrum of biological actions that also includes induction of cell proliferation, immunomodulation, and control of other hormonal systems. Many cells that play an important role in the cardiovascular system express the Vitamin D receptor (VDR) and respond to 1,25-(OH)2D (the active product of vitamin D conversion by hydroxylase) with cell-specific function and gene regulation. These cells include cardiomyocytes, vascular endothelial cells, vascular smooth muscle cells, phagocytes, and cells of the nephron, which produce renin. VDR activators (calcitriol and paricalcitol) are available for the treatment of vitamin D deficiency, which can result from inadequate cutaneous production and/or low dietary intake. Vitamin-D deficient patients present a higher risk of cardiovascular disease than the general population. Recent clinical observations have shown that VDR activator therapy provides survival benefit and also has a positive impact on cardiovascular function. Compelling results have arisen from previous studies of mice with disrupted genes of the vitamin D signaling pathways. In mice lacking VDR or CYP27B1 (1α-hydroxylase - an enzyme, which converts vitamin D to its active form), in addition to the expected phenotype (hypocalcaemia, secondary hyperparathyroidism and osteomalacia), development of hypertension and cardiac hypertrophy were also observed. Moreover, these mice presented with overexpression of renin and atrial natriuretic peptide. VDR may play a role in regulating smooth-muscle-cell (SMC) proliferation, thrombosis, fibrinolysis and vessel relaxation. The influence of VDR activators on the modulation of renin expression and vascular function may reduce mortality, organ damage, and cardiovascular morbidity in VDR-activator-treated patients with hypertension. Since clinical use of calcitriol is largely limited, because of the side effect of hypercalcemia, calcitriol analogues have been synthesized to obtain compounds with better therapeutic profiles. The main purpose of this article is to review the role of vitamin D and vitamin D receptor activators in cardiovascular diseases, especially hypertension and its treatment. Due to the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D supplementation therapy may be warranted in this population.

Acoustic startle responses and prepulse inhibition of acoustic startle responses in Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats.

AIMS: An assessment of the acoustic startle response (ASR) and prepulse inhibition (PPI) of ASR in laboratory animals is used to model human anxiety and psychotic states, respectively. The aim of the study was to evaluate ASR and PPI in alcohol-naive male and female Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats. METHODS: ASR and PPI were assessed in two separate experiments by using the SR-LAB apparatus (San Diego Instruments, San Diego, CA, USA). In the ASR session, animals (n = 13-16 rats per group) were exposed to startling stimuli of different intensities (72, 84, 98, 112 and 124 dB) in a random order. In the PPI session, prepulse stimuli (78, 81, 84 and 90 dB) preceded a pulse startling stimulus (120 dB) in a random order. The background white noise was set at 70 dB. PPI was calculated according to the formula: [(startle amplitude in pulse alone trials-startle amplitude in prepulse-and-pulse trials)/startle amplitude in pulse alone trials] 100%. RESULTS: The WHP males exhibited higher startle amplitudes in response to 112 dB stimuli when compared with their WLP counterparts. The WHP females showed higher startle reactivity to 112 and 124 dB stimuli when compared with the WLP females. There were no differences between the WHPs and WLPs in PPI of ASR. CONCLUSION: The results of the present study suggest that exaggerated startle responses can be a physiological/behavioral marker of a propensity to abuse alcohol.

Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data.

Mental disorders, such as depression and anxiety, pose both medical and social challenges. The clinical efficacy of current antidepressant/anxiolytic therapies is unsatisfactory; both antidepressant and anxiolytic drugs induce a variety of unwanted effects and have delayed onsets of action. Thus, a search for better and safer agents is continuously in progress. Preclinical results published so far have brought new insights into the possible role of recently discovered serotonin 5-HT(6) receptors in these disorders. This review surveys the current state of knowledge regarding potential antidepressant and anxiolytic activities of selective 5-HT(6) receptor ligands, namely, full agonists and antagonists, in animal models commonly used to predict such activity. Evidence indicates that both 5-HT(6) agonists and antagonists may evoke identical responses in animal models of depression and anxiety; however, the possible mechanisms of these effects seem to be diverse and are not clearly understood. Especially interesting are the augmented effects achieved by combining antidepressants or diazepam with a selective 5-HT(6) receptor antagonist.

Synthesis and 5-HT(1A), 5-HT(2A) receptor activity of new beta-tetralonohydantoins.

A series of new 3-[4-(4-arylpiperazinyl)-butyl]-beta-tetralonohydantoins (8a-13a) were synthesized. The compounds exhibited high affinity for 5-HT(1A) receptors (K(i)=6 to 55 nM) combined with moderate-to-high 5-HT(2A) receptor affinities (K(i)=45 to 213 nM). The results of in vivo studies indicated that of the compounds tested, 3-[4-(4-phenylpiperazinyl)-butyl-beta-tetralonohydantoin (8a) showed features of full (pre- and postsynaptic) 5-HT(1A) receptor agonists, whereas compounds 9a-13a behaved like antagonists of postsynaptic 5-HT(1A) receptors; additionally, compound 13a produced an effect characteristic of presynaptic 5-HT(1A) receptor agonists. Moreover, compounds 8a and 10a-13a exhibited properties of 5-HT(2A) receptor antagonists. Due to the most interesting 5-HT(1A)/5-HT(2A) functional profile compounds 8a and 13a were further tested for their potential psychotropic activity. In fact, compound 8a (but not 13a) showed diazepam-like anxiolytic activity and behaved like a weak antidepressant.