scholarly journals New Insights into the Stereochemical Requirements of the Bombesin BB1 Receptor Antagonists Binding

2020 ◽  
Vol 13 (8) ◽  
pp. 197
Author(s):  
Bahareh Rasaeifar ◽  
Patricia Gomez-Gutierrez ◽  
Juan J. Perez
Keyword(s):  
Biological Activities ◽  
Docking Study ◽  
Experimental Information ◽  
Peptide Ligands ◽  
Peripheral Tissues ◽  
Starting Point ◽  
Wide Range ◽  
The Family ◽  
The Central Nervous System ◽  
G Protein Coupled

Members of the family of bombesinlike peptides exert a wide range of biological activities both at the central nervous system and in peripheral tissues through at least three G-Protein Coupled Receptors: BB1, BB2 and BB3. Despite the number of peptide ligands already described, only a few small molecule binders have been disclosed so far, hampering a deeper understanding of their pharmacology. In order to have a deeper understanding of the stereochemical features characterizing binding to the BB1 receptor, we performed the molecular modeling study consisting of the construction of a 3D model of the receptor by homology modeling followed by a docking study of the peptoids PD168368 and PD176252 onto it. Analysis of the complexes permitted us to propose prospective bound conformations of the compounds, consistent with the experimental information available. Subsequently, we defined a pharmacophore describing minimal stereochemical requirements for binding to the BB1 receptor that was used in silico screening. This exercise yielded a set of small molecules that were purchased and tested, showing affinity to the BB1 but not to the BB2 receptor. These molecules exhibit scaffolds of diverse chemical families that can be used as a starting point for the development of novel BB1 antagonists.

scholarly journals Are GPCRs Still a Source of New Targets?

2013 ◽  
Vol 18 (9) ◽  
pp. 947-966 ◽  
Author(s):  
Stephen L. Garland
Keyword(s):  
Drug Targets ◽  
Protein Complexes ◽  
X Ray Crystallography ◽  
Peptide Family ◽  
Wide Range ◽  
The Family ◽  
Receptor Pharmacology ◽  
Technical Advances ◽  
Allosteric Mechanisms ◽  
G Protein Coupled

G-protein–coupled receptors (GPCRs) still offer enormous scope for new therapeutic targets. Currently marketed agents are dominated by those with activity at aminergic receptors and yet they account for only ~10% of the family. Progress up until now with other subfamilies, notably orphans, Family A/peptide, Family A/lipid, Family B, Family C, and Family F, has been, at best, patchy. This may be attributable to the heterogeneous nature of GPCRs, their endogenous ligands, and consequently their binding sites. Our appreciation of receptor similarity has arguably been too simplistic, and screening collections have not necessarily been well suited to identifying leads in new areas. Despite the relative shortage of high-quality tool molecules in a number of cases, there is an emerging, and increasingly substantial, body of evidence associating many as yet “undrugged” receptors with a very wide range of diseases. Significant advances in our understanding of receptor pharmacology and technical advances in screening, protein X-ray crystallography, and ligand design methods are paving the way for new successes in the area. Exploitation of allosteric mechanisms; alternative signaling pathways such as G12/13, Gβγ, and β-arrestin; the discovery of “biased” ligands; and the emergence of GPCR-protein complexes as potential drug targets offer scope for new and much improved drugs.

scholarly journals Distribution of the prion protein in sheep terminally affected with BSE following experimental oral transmission

2001 ◽  
Vol 82 (10) ◽  
pp. 2319-2326 ◽  
Author(s):  
J. D. Foster ◽  
D. W. Parnham ◽  
N. Hunter ◽  
M. Bruce
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Experimental Infection ◽  
Oral Route ◽  
Similar Distribution ◽  
Peripheral Tissues ◽  
Oral Transmission ◽  
Wide Range ◽  
Direct Contrast ◽  
The Central Nervous System

This study has examined the distribution of PrPSc in sheep by immunocytochemistry of tissues recovered from terminally affected animals following their experimental infection by the oral route with BSE. Despite a wide range of incubation period lengths, affected sheep showed a similar distribution of high levels of PrPSc throughout the central nervous system. PrPSc was also found in the lymphoid system, including parts of the digestive tract, and some components of the peripheral nervous system. These abundant PrPSc deposits in sheep in regions outside the central nervous system are in direct contrast with cattle infected with BSE, which show barely detectable levels of PrPSc in peripheral tissues. A number of genetically susceptible, challenged animals appear to have survived.

Family-Based Project Approach to Multidisciplinary Senior Design

2008 ◽  
Author(s):  
Wayne Walter ◽  
Edward Hensel
Keyword(s):  
Undergraduate Students ◽  
Lessons Learned ◽  
Open Architecture ◽  
Current Status ◽  
Senior Design ◽  
Starting Point ◽  
Wide Range ◽  
The Family ◽  
Design Projects ◽  
Academic Year

During academic year 2006–07, a family of four closely related multi-disciplinary senior design projects was initiated. Each project team consisted of eight undergraduate students. The family of projects has continued during the academic year 2007–08, with three additional design projects comprised of 19 students. The intent of the family of design projects is two-fold. The first objective is to introduce students to the concept of designing a product within the context of a family of closely related products, similar to the approach that a corporation may use in its strategic approach to the marketplace. The second objective is to provide an open-source, open-architecture, modular, and scalable robotic vehicle platform usable by a wide range of researchers within the Kate Gleason College of Engineering looking for a vehicle to position cameras, sensors in networks, and for other data-gathering tasks. Students were given the challenge to design and manufacture a platform based on a single design, scalable across four payload orders of magnitude from 1kg to 1,000kg. The 10kg and 100kg variants were studied in AY2006–07, and the 1kg variant was introduced in AY2007–08. The largest, 1,000kg, planned for the future, will be about the size of a Honda Civic, so safety and fail-safe engineering is important. Each project in the family is expected to build on the technology used and lessons learned from prior and concurrent projects, much like the “next model year” in the auto industry, and information sharing requirements among concurrent engineering teams. Hardware, software, and design methods are reused whenever possible, and students are expected to develop their subsystem in the context of an evolutionary platform design. In this manner, the end-product from one design group becomes the starting point for another team. Responsibilities overlap so teams must work cooperatively, which mimics the industrial environment. Starting times on various projects may be staggered, and students must deal with documentation sharing issues, and preservation of design intent across multiple-project teams and academic terms. The paper will discuss the current status of the program, the lessons learned to-date, and future plans for the program.

(Hetero)Aryloxyaminopropanols with N-Phenylpiperazine Structural Fragment – Review of Cardiovascular Activity

2020 ◽  
Vol 20 (17) ◽  
pp. 1719-1731
Author(s):  
Pavlina Marvanova ◽  
Tereza Padrtova ◽  
Petr Mokry
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Biological Activities ◽  
Cardiovascular Effects ◽  
Structural Fragment ◽  
Cardiovascular Activity ◽  
Phosphodiesterase Inhibition ◽  
Cardiovascular Agents ◽  
Wide Range ◽  
The Central Nervous System

Aryloxyphenylpiperazinylpropanols are a group of compounds exhibiting a wide range of biological activities, affecting the central nervous system and many cardiovascular mechanisms among them. As cardiovascular agents, aryloxyphenylpiperazinylpropanols work as antihypertensives, antiarrhythmics, cardiotonics or antiaggregants. The mechanism of action is almost always an α1-adrenolytic or combined α1- and β-adrenolytic effect, but sometimes other mechanisms (e.g., Ca2+ antagonism or phosphodiesterase inhibition) antagonism or phosphodiesterase inhibition) can positively participate. In some cases, compounds with a small modification of the connecting chain also exhibit the desired cardiovascular effects. Several studies dealt with chirality of aryloxyphenylpiperazinylpropanols and determined the differences between the particular activities of racemic and enantiomeric compounds.

Orexin 2 Receptor (OX2R) Protein Distribution Measured by Autoradiography Using Radiolabeled OX2R-Selective Antagonist EMPA in Rodent Brain and Peripheral Tissues

2021 ◽  
Author(s):  
Kayo Mitsukawa ◽  
Haruhide Kimura
Keyword(s):  
Brain Slices ◽  
Brain Regions ◽  
Retrosplenial Cortex ◽  
Biological Functions ◽  
Protein Distribution ◽  
Peripheral Tissues ◽  
Physiological Functions ◽  
Wide Range ◽  
The Central Nervous System

Abstract Orexin, a neuropeptide, performs various physiological functions, including the regulation of emotion, feeding, metabolism, respiration, and sleep/wakefulness, by activating the orexin 1 receptor and orexin 2 receptor (OX2R). Owing to the pivotal role of OX2R in wakefulness and other biological functions, OX2R agonists are being developed. A detailed understanding of OX2R protein distribution is essential for determining the mechanisms of action of OX2R agonists; however, this has been hindered by the lack of selective antibodies. In this study, we first confirmed the OX2R-selective binding of [3H]-EMPA in in vitro autoradiography studies, using brain slices from OX2R knockout mice and their wild-type littermates. Subsequently, OX2R protein distribution in rats was comprehensively assessed in 51 brain regions and 10 peripheral tissues using in vitro autoradiography with [3H]-EMPA. The widespread distribution of OX2R protein, including that in previously unrecognized regions of the retrosplenial cortex and suprachiasmatic nucleus of the hypothalamus, was identified. In contrast, negligible/very low OX2R protein expression was observed in peripheral tissues, suggesting that orexin exerts OX2R-dependent physiological functions primarily through activation of the central nervous system. These data would be useful for understanding the wide range of biological functions of OX2R and the application of OX2R agonists in various disorders.

Turmeric

2020 ◽  
pp. 163-172
Author(s):  
Mazia Ahmed ◽  
Urvashi Srivastava ◽  
Chitra Gupta
Keyword(s):  
Biological Activities ◽  
Curcuma Longa ◽  
Healthy Food ◽  
Natural Food ◽  
Food Ingredient ◽  
Tropical Regions ◽  
Naturally Occurring ◽  
Diverse Field ◽  
Wide Range ◽  
The Family

Turmeric (Curcuma longa) is a rhizomatous crop found in tropical regions and belongs to the family Zingiberaceae. It was used in the form of a spice, flavoring substance, coloring agent, and as a therapeutic agent for the treatment of several human ailments for centuries. Turmeric, along with its extracts, has a very broad and diverse field of application. It is an exclusive and versatile naturally occurring plant product having properties of not only a spice but also food colorant, medicine or drug, and cosmetics. In ethnic delicacies, turmeric is a commonly used flavoring ingredient. It is also a popularly used natural food color. It exhibits several biological activities such as having antioxidant, anti-inflammatory, anticarcinogenic, antimutagenic, antimicrobial, antiviral, and antiparasitic properties. It is well known as a skincare product and a healthy food ingredient. It is found to have the capability to prevent or retard a wide range of ailments.

scholarly journals Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia

2021 ◽  
Author(s):  
Katarzyna Chamera ◽  
Magdalena Szuster-Głuszczak ◽  
Agnieszka Basta-Kaim
Keyword(s):  
Experimental Studies ◽  
Physiological Processes ◽  
Unique System ◽  
The Family ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
G Protein Coupled ◽  
The Brain ◽  
Brain Homeostasis

AbstractSchizophrenia has a complex and heterogeneous molecular and clinical picture. Over the years of research on this disease, many factors have been suggested to contribute to its pathogenesis. Recently, the inflammatory processes have gained particular interest in the context of schizophrenia due to the increasing evidence from epidemiological, clinical and experimental studies. Within the immunological component, special attention has been brought to chemokines and their receptors. Among them, CX3C chemokine receptor 1 (CX3CR1), which belongs to the family of seven-transmembrane G protein-coupled receptors, and its cognate ligand (CX3CL1) constitute a unique system in the central nervous system. In the view of regulation of the brain homeostasis through immune response, as well as control of microglia reactivity, the CX3CL1–CX3CR1 system may represent an attractive target for further research and schizophrenia treatment. In the review, we described the general characteristics of the CX3CL1–CX3CR1 axis and the involvement of this signaling pathway in the physiological processes whose disruptions are reported to participate in mechanisms underlying schizophrenia. Furthermore, based on the available clinical and experimental data, we presented a guide to understanding the implication of the CX3CL1–CX3CR1 dysfunctions in the course of schizophrenia.

Hormonal Interactions in the Effects of Halogenated Aromatic Hydrocarbons On the Developing Brain

1998 ◽  
Vol 14 (1-2) ◽  
pp. 185-208 ◽  
Author(s):  
Neil J. Maclusky ◽  
Theodore J. Brown ◽  
Susan Schantz ◽  
Byung Woun Seo ◽  
Richard E. Peterson
Keyword(s):  
Low Dose ◽  
Biological Activities ◽  
Developing Brain ◽  
Adrenocortical Function ◽  
Environmental Toxicants ◽  
Halogenated Aromatic Hydrocarbons ◽  
Wide Range ◽  
The Central Nervous System ◽  
Dioxin Exposure ◽  
Underlying Mechanisms

Halogenated arylhydrocarbons (HAHs) exert a wide range of effects on the developing brain. These effects result in altered patterns of neuroendocrine function and behavior in adulthood, as well as changes in cognitive function. The underlying mechanisms have not yet been clearly defined. This paper briefly reviews the effects of HAHs on brain development, and proposes the hypothesis that interactions between different hormone-sensitive systems may contribute to the broad spectrum of responses observed after fetal or early postnatal HAH exposure. Physiological interactions between the effects of sex steroids, corticosteroids, and thyroid hormone are known to influence the development of the central nervous system (CNS). Since the biosynthesis and/or action of each of these hormones is sensitive to developmental HAH exposure, it is suggested that convergent effects of HAHs on different endocrine pathways may underlie some of the disruptive effects of these chemicals on CNS differentiation. Data are presented indicating that the disruptive effects of low dose dioxin exposure on sexual differentiation of the rat brain are probably not mediated through blockade of estrogen responses, butmay instead involve subtle developmental changes in other endocrine systems, perhaps also affecting the feedback control of adrenocortical function. The potential for interactive endocrine effects illustrates the need for a fuller understanding of the range of biological activities of HAHs in the brain, so that the potential risks of low dose developmental exposure to these environmental toxicants can be predicted with greater certainty.

scholarly journals The Role of TRP Channels in Migraine

2013 ◽  
Vol 6 (1) ◽  
pp. 37-49 ◽  
Author(s):  
Gerry Stephen Oxford ◽  
Joyce Harts Hurley
Keyword(s):  
Trp Channels ◽  
Large Family ◽  
Trigeminovascular System ◽  
Peripheral Tissues ◽  
Wide Range ◽  
The Family ◽  
The Status ◽  
Physical Stimuli ◽  
Pain Transduction

TRP channels are members of a large family of non-selective cation channels. The family which numbers over 30 is classified into 6 groups based on amino acid sequence homology. TRP channels are distributed in many peripheral tissues as well as central and peripheral nervous system. These channels are important in sensing a wide range of chemical and physical stimuli. Several TRP channels, including TRPV1 and TRPA1 are important in pain transduction pathways. This review will focus on the function of TRP channels in the trigeminovascular system and other anatomical regions which are relevant to migraine. We will discuss the possible role of TRP channels in migraine, including the potential role of TRPV1 in the hypersensitivity and allodynia frequently observed in migraine patients. We will review the status of TRP channel drugs in migraine therapeutics. We will also discuss the possible roles of TRP channels in triggering migraine attacks, a process which is not well-understood.

scholarly journals Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction

2020 ◽  
Vol 12 ◽  
Author(s):  
Claudia Sagheddu ◽  
Larissa Helena Torres ◽  
Tania Marcourakis ◽  
Marco Pistis
Keyword(s):  
Psychiatric Disorders ◽  
Biological Activities ◽  
Signaling System ◽  
Physiological Processes ◽  
Naturally Occurring ◽  
The Family ◽  
Complex Lipid ◽  
The Central Nervous System ◽  
Dopamine Signaling

The family of lipid neuromodulators has been rapidly growing, as the use of different -omics techniques led to the discovery of a large number of naturally occurring N-acylethanolamines (NAEs) and N-acyl amino acids belonging to the complex lipid signaling system termed endocannabinoidome. These molecules exert a variety of biological activities in the central nervous system, as they modulate physiological processes in neurons and glial cells and are involved in the pathophysiology of neurological and psychiatric disorders. Their effects on dopamine cells have attracted attention, as dysfunctions of dopamine systems characterize a range of psychiatric disorders, i.e., schizophrenia and substance use disorders (SUD). While canonical endocannabinoids are known to regulate excitatory and inhibitory synaptic inputs impinging on dopamine cells and modulate several dopamine-mediated behaviors, such as reward and addiction, the effects of other lipid neuromodulators are far less clear. Here, we review the emerging role of endocannabinoid-like neuromodulators in dopamine signaling, with a focus on non-cannabinoid N-acylethanolamines and their receptors. Mounting evidence suggests that these neuromodulators contribute to modulate synaptic transmission in dopamine regions and might represent a target for novel medications in alcohol and nicotine use disorder.

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