Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?

Chromone-3-phenylcarboxamides (Crom-1 and Crom-2) were identified as potent, selective, and reversible inhibitors of human monoamine oxidase B (hMAO-B). Since they exhibit some absorption, distribution, metabolism, and excretion (ADME)-toxicity liabilities, new derivatives were synthesized to map the chemical structural features that compose the pharmacophore, a process vital for lead optimization. Structure-activity relationship data, supported by molecular docking studies, provided a rationale for the contribution of the heterocycle's rigidity, the carbonyl group, and the benzopyran heteroatom for hMAO-B inhibitory activity. From the study, N-(3-chlorophenyl)-4H-thiochromone-3-carboxamide (31) (hMAO-B IC50 = 1.52 ± 0.15 nM) emerged as a reversible tight binding inhibitor with an improved pharmacological profile. In in vitro ADME-toxicity studies, compound 31 showed a safe cytotoxicity profile in Caco-2, SH-SY5Y, HUVEC, HEK-293, and MCF-7 cells, did not present cardiotoxic effects, and did not affect P-gp transport activity. Compound 31 also protected SH-SY5Y cells from iron(III)-induced damage. Collectively, these studies highlighted compound 31 as the first-in-class and a suitable candidate for in vivo preclinical investigation.

Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders.

ABC (ATP-binding cassette) transporters represent one of the largest and most diverse superfamily of proteins in living species, playing an important role in many biological processes such as cell homeostasis, cell signaling, drug metabolism and nutrient uptake. Moreover, using the energy generated from ATP hydrolysis, they mediate the efflux of endogenous and exogenous substrates from inside the cells, thereby reducing their intracellular accumulation. At present, 48 ABC transporters have been identified in humans, which were classified into 7 different subfamilies (A to G) according to their phylogenetic analysis. Nevertheless, the most studied members with importance in drug therapeutic efficacy and toxicity include P-glycoprotein (P-gp), a member of the ABCB subfamily, the multidrug-associated proteins (MPRs), members of the ABCC subfamily, and breast cancer resistance protein (BCRP), a member of the ABCG subfamily. They exhibit ubiquitous expression throughout the human body, with a special relevance in barrier tissues like the blood-brain barrier (BBB). At this level, they play a physiological function in tissue protection by reducing or limiting the brain accumulation of neurotoxins. Furthermore, dysfunction of ABC transporters, at expression and/or activity level, has been associated with many neurological diseases, including epilepsy, multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. Additionally, these transporters are strikingly associated with the pharmacoresistance to central nervous system (CNS) acting drugs, because they contribute to the decrease in drug bioavailability. This article reviews the signaling pathways that regulate the expression and activity of P-gp, BCRP and MRPs subfamilies of transporters, with particular attention at the BBB level, and their mis-regulation in neurological disorders.

Design of novel monoamine oxidase-B inhibitors based on piperine scaffold: Structure-activity-toxicity, drug-likeness and efflux transport studies.

Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 µM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC50 = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.

Empirically supported interventions in psychology: contributions of Research Domain Criteria

Abstract Empirically supported interventions in psychological disorders should provide (1) evidence supporting the underlying psychological mechanisms of psychopathology to target in the intervention and (2) evidence supporting the efficacy of the intervention. However, research has been dedicated in a greater extent to efficacy than to the acquisition of empirical support for the theoretical basis of therapies. Research Domain Criteria (RDoC) emerges as a new framework to provide empirically based theories about psychological mechanisms that may be targeted in intervention and tested for its efficacy. The current review aims to demonstrate the possible applications of RDoC to design empirically supported interventions for psychological disorders. Two RDoC-inspired interventions are reviewed, and the RDoC framework is broadly explored in terms of its contributions and limitations. From preliminary evidence, RDoC offers many avenues for improving evidence-based interventions in psychology, but some limitations must be anticipated to increase the RDoC applicability to naturalistic settings. (AU)

New version of the emotion socialization scale with the positive emotion of overjoy: initial validation evidence with Portuguese adolescents

Abstract There are few studies on parental socialization of positive emotions in adolescents and few instruments that measure these parental reactions. Therefore, we developed a new version of the Emotion Socialization Scale (ESS) for the positive emotion of overjoy. We further provided some evidence of validity and reliability of the Portuguese ESS, featuring overjoy, fear, anger, and sadness. Adolescents (N = 418) answered questionnaires on maternal emotion socialization and maternal rearing practices. Confirmatory factor analysis achieved good (reward, neglect, override, magnify) to acceptable (punish) levels of fit, and scales had good levels of internal consistency, except for punish (all emotions) and neglect (overjoy). Association with maternal rearing practices supported the adaptive role of reward and magnify and the less adaptive role of punish, override, neglect of positive emotion, with some exceptions. This investigation demonstrated the importance of assessing parents' reactions to adolescents' positive emotion as these may be important indicators of the parent-adolescent relationship quality.

Vibrio diabolicus challenge in Bathymodiolus azoricus populations from Menez Gwen and Lucky Strike hydrothermal vent sites.

Menez Gwen (MG) and Lucky Strike (LS) deep-sea hydrothermal vents are located at 850 m and 1730 m depths respectively and support chemosynthesis-based ecosystems partially differing in heavy metal concentration, temperature range, and faunistic composition. The successfully adapted deep-sea vent mussel Bathymodiolus azoricus is found at both vent locations. In such inhospitable environments survival strategies rely on the establishment of bacteria-vent animal symbiosis In spite of the toxic nature of deep-sea vents, the problem of microbial threat and the need for immunity exist in B. azoricus. This study aims at investigating the immune system of B. azoricus from MG and LS populations by comparing immune gene expressions profiles using the deep-sea vent-related Vibrio diabolicus. Expression of nineteen immune genes was analyzed from gill, digestive gland and mantle tissues upon 3 h, 12 h and 24 h V. diabolicus challenges. Based on quantitative-Polymerase Chain Reaction (qPCR) significant gene expression differences were found among MG and LS populations and challenge times MG mussels revealed that gill and digestive gland gene expression levels were remarkably higher than those from LS mussels. Expression of Carcinolectin, Serpin-2, SRCR, IRGs, RTK, TLR2, NF-κB, HSP70 and Ferritin genes was greater in MG than LS mussels. In contrast, mantle tissue from LS mussels revealed the highest peak of expression at 24 h for most genes analyzed. The activation of immune signaling pathways demonstrated that gene expression profiles are distinct between the two mussel populations. These differences may possibly ensue from intrinsic immune transcriptional activities upon which host responses are modulated in presence of V. diabolicus. mRNA transcript variations were assessed during 24 h acclimatization taking into account the partial depuration to which mussels were subjected to. Additionally, gene expression differences may reflect still accountable effects from the presence of vent remaining microfluidic environments within the tissues analyzed.