scholarly journals Current Concepts and Treatments of Schizophrenia

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2087 ◽  
Author(s):  
Piotr Stępnicki ◽  
Magda Kondej ◽  
Agnieszka A. Kaczor
Keyword(s):  
Social Withdrawal ◽  
G Protein Coupled Receptors ◽  
Positive Symptoms ◽  
Allosteric Modulators ◽  
Attention Disorders ◽  
Flat Affect ◽  
Receptor Oligomerization ◽  
Signaling Mechanisms ◽  
Thought Disorders ◽  
G Protein Coupled

Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.

scholarly journals Integrating High-Content Analysis into a Multiplexed Screening Approach to Identify and Characterize GPCR Agonists

2014 ◽  
Vol 19 (7) ◽  
pp. 1079-1089 ◽  
Author(s):  
Yingjie Zhu ◽  
John Watson ◽  
Mengjie Chen ◽  
Ding Ren Shen ◽  
Melissa Yarde ◽  
...  
Keyword(s):  
Drug Discovery ◽  
G Protein Coupled Receptors ◽  
High Content Imaging ◽  
Biased Agonism ◽  
Receptor Oligomerization ◽  
Sphingosine 1 Phosphate ◽  
High Content Analysis ◽  
Screening Assays ◽  
Hit Identification ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are one of the most popular and proven target classes for therapeutic intervention. The increased appreciation for allosteric modulation, receptor oligomerization, and biased agonism has led to the development of new assay platforms that seek to capitalize on these aspects of GPCR biology. High-content screening is particularly well suited for GPCR drug discovery given the ability to image and quantify changes in multiple cellular parameters, to resolve subcellular structures, and to monitor events within a physiologically relevant environment. Focusing on the sphingosine-1-phosphate (S1P1) receptor, we evaluated the utility of high-content approaches in hit identification efforts by developing and applying assays to monitor β-arrestin translocation, GPCR internalization, and GPCR recycling kinetics. Using these approaches in combination with more traditional GPCR screening assays, we identified compounds whose unique pharmacological profiles would have gone unnoticed if using a single platform. In addition, we identified a compound that induces an atypical pattern of β-arrestin translocation and GPCR recycling kinetics. Our results highlight the value of high-content imaging in GPCR drug discovery efforts and emphasize the value of a multiassay approach to study pharmacological properties of compounds of interest.

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

2021 ◽  
Author(s):  
Eva Dolejší ◽  
Eszter Szánti-Pintér ◽  
Nikolai Chetverikov ◽  
Dominik Nelic ◽  
Alena Randáková ◽  
...  
Keyword(s):  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Allosteric Modulators ◽  
The Novel ◽  
Stress Control ◽  
Structure Activity ◽  
G Protein Coupled

Abstract The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone, and some neurosteroids bound to muscarinic receptors with an affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

G-protein-coupled receptor allosterism: the promise and the problem(s)

2004 ◽  
Vol 32 (5) ◽  
pp. 873-877 ◽  
Author(s):  
A. Christopoulos ◽  
L.T. May ◽  
V.A. Avlani ◽  
P.M. Sexton
Keyword(s):  
G Protein ◽  
Binding Sites ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Screening Methods ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Physiological Regulation ◽  
Subtype Selectivity ◽  
G Protein Coupled

Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more ‘physiological’ regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

2015 ◽  
Vol 353 (2) ◽  
pp. 246-260 ◽  
Author(s):  
Emma T. van der Westhuizen ◽  
Celine Valant ◽  
Patrick M. Sexton ◽  
Arthur Christopoulos
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Allosteric Modulators ◽  
G Protein Coupled

scholarly journals Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation: Part 2

2018 ◽  
Vol 38 (04) ◽  
pp. 211-222
Author(s):  
Rüdiger Scharf
Keyword(s):  
Thrombus Formation ◽  
Fluid Phase ◽  
G Protein Coupled Receptors ◽  
Microbial Pathogens ◽  
Extracellular Traps ◽  
Signaling Mechanisms ◽  
Arterial Thrombus ◽  
Platelet Signaling ◽  
Genetically Determined ◽  
G Protein Coupled

AbstractPlatelet signal transduction is the focus of this review. While ‘classic’ platelet signaling through G protein–coupled receptors in response to fluid-phase agonists has been extensively studied, signaling mechanisms linking platelet adhesion receptors such as GPIb-IX-V, GPVI and α2β1 to the activation of αIIbβ3 are less well established. Moreover, ‘non-haemostatic’ pathways can also activate platelets in various settings, including platelet–immune or platelet–tumour cell interactions, platelet responses to neutrophil extracellular traps, or stimulation by microbial pathogens. Genetically determined integrin variants can modulate platelet function and increase thrombogenicity. A typical example is the Pro33 (HPA-1b) variant of αIIbβ3. Recent advances in the genotype–phenotype relation of this prothrombotic variant and its impact on outside-in signaling will be reviewed.

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