scholarly journals Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development

2019 ◽  
Vol 19 (16) ◽  
pp. 1381-1398 ◽  
Author(s):  
Eric A. Wold ◽  
Christopher T. Wild ◽  
Kathryn A. Cunningham ◽  
Jia Zhou
Keyword(s):  
Biological Significance ◽  
Current Status ◽  
Allosteric Modulators ◽  
Class A ◽  
Current State ◽  
The Central Nervous System ◽  
Treatment Of Obesity ◽  
And Function ◽  
Anxiety Depression ◽  
G Protein Coupled

Serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is recognized as a critical mediator of diseaserelated pathways and behaviors based upon actions in the central nervous system (CNS). Since 5-HT2CR is a class A G protein-coupled receptor (GPCR), drug discovery efforts have traditionally pursued the activation of the receptor through synthetic ligands with agonists proposed for the treatment of obesity, substance use disorders and impulse control disorders while antagonists may add value for the treatment of anxiety, depression and schizophrenia. The most significant agonist discovery to date is the FDAapproved anti-obesity medication lorcaserin. In recent years, efforts towards developing other mechanisms to enhance receptor function have resulted in the discovery of Positive Allosteric Modulators (PAMs) for the 5-HT2CR, with several molecule series now reported. The biological significance and context for signaling and function of the 5-HT2CR, and the current status of 5-HT2CR agonists and PAMs are discussed in this review.

scholarly journals Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 834
Author(s):  
Anima M. Schäfer ◽  
Henriette E. Meyer zu Schwabedissen ◽  
Markus Grube
Keyword(s):  
Organic Anion ◽  
Physiological Role ◽  
Point Of View ◽  
Efflux Transporters ◽  
Organic Anion Transporting Polypeptides ◽  
Current State ◽  
P Glycoprotein ◽  
The Central Nervous System ◽  
And Function ◽  
Uptake Transporters

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

scholarly journals Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lei Liu ◽  
Zhiran Fan ◽  
Xavier Rovira ◽  
Li Xue ◽  
Salomé Roux ◽  
...  
Keyword(s):  
Binding Site ◽  
Drug Targets ◽  
Transmembrane Domain ◽  
Transmembrane Domains ◽  
Site Directed Mutagenesis ◽  
Fine Tuning ◽  
Ion Binding ◽  
Allosteric Modulators ◽  
Class A ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are among the most promising drug targets. They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes to fine tuning of transmembrane signaling. Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their physiological roles and to validate them as drug targets. Here, we examined the mode of action of positive allosteric modulators (PAMs) that bind at the interface of the transmembrane domains of the heterodimeric GABAB receptor. Our site-directed mutagenesis results show that mutations of this interface impact the function of the three PAM tested. The data support the inference that they act at the active interface between both transmembrane domains, the binding site involving residues of the TM6s of the GABAB1 and the GABAB2 subunit. Importantly, the agonist activity of these PAMs involves a key region in the central core of the GABAB2 transmembrane domain, which also controls the constitutive activity of the GABAB receptor. This region corresponds to the sodium ion binding site in class A GPCRs that controls the basal state of the receptors. Overall, these data reveal the possibility of developing allosteric compounds able to specifically modulate the activity of GPCR homo- and heterodimers by acting at their transmembrane interface.

scholarly journals Structural Basis for Allosteric Modulation of Class B G Protein–Coupled Receptors

2020 ◽  
Vol 60 (1) ◽  
pp. 89-107 ◽  
Author(s):  
Denise Wootten ◽  
Laurence J. Miller
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Allosteric Modulators ◽  
Class B ◽  
Endogenous Proteins ◽  
And Function ◽  
Agonist Ligands ◽  
G Protein Coupled

Recent advances in our understanding of the structure and function of class B G protein–coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies.

RGS proteins: identifying new GAPs in the understanding of blood pressure regulation and cardiovascular function

2009 ◽  
Vol 116 (5) ◽  
pp. 391-399 ◽  
Author(s):  
Steven Gu ◽  
Carlo Cifelli ◽  
Sean Wang ◽  
Scott P. Heximer
Keyword(s):  
Blood Pressure ◽  
G Protein ◽  
Uncontrolled Hypertension ◽  
Rgs Proteins ◽  
Treatment And Prevention ◽  
Current State ◽  
G Protein Signalling ◽  
Prevention Of Hypertension ◽  
And Function ◽  
G Protein Coupled

Understanding the mechanisms that underlie BP (blood pressure) variation in humans and animal models may provide important clues for reducing the burden of uncontrolled hypertension in industrialized societies. High BP is often associated with increased signalling via G-protein-coupled receptors. Three members of the RGS (regulator of G-protein signalling) superfamily RGS2, RGS4 and RGS5 have been implicated in the attenuation of G-protein signalling pathways in vascular and cardiac myocytes, as well as cells of the kidney and autonomic nervous system. In the present review, we discuss the current state of knowledge regarding their differential expression and function in cardiovascular tissues, and the likelihood that one or more of these alleles are candidate hypertension genes. Together, findings from the studies described herein suggest that development of methods to modulate the expression and function of RGS proteins may be a possible strategy for the treatment and prevention of hypertension and cardiovascular disease.

Insights into the activation mechanism of the visual receptor rhodopsin

2012 ◽  
Vol 40 (2) ◽  
pp. 389-393 ◽  
Author(s):  
Steven O. Smith
Keyword(s):  
Structural Biology ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Class A ◽  
Highly Sensitive ◽  
The Common ◽  
Dim Light ◽  
And Function ◽  
G Protein Coupled ◽  
Visual Receptor

Recent advances in the structural biology of GPCRs (G-protein-coupled receptors) have provided insights into their structure and function. Comparisons of the visual and ligand-activated receptors highlight the unique elements of rhodopsin that allow it to function as a highly sensitive dim-light photoreceptor in vertebrates, as well as the common elements that it shares with the large class A GPCR family. However, despite progress, a number of questions remain unanswered about how these receptors are activated.

scholarly journals The GABAB Receptor—Structure, Ligand Binding and Drug Development

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3093
Author(s):  
Linn Samira Mari Evenseth ◽  
Mari Gabrielsen ◽  
Ingebrigt Sylte
Keyword(s):  
Transmembrane Domain ◽  
Gabab Receptor ◽  
Inhibitory Neurotransmitter ◽  
Receptor Structure ◽  
Future Drug ◽  
The Central Nervous System ◽  
Broad Variety ◽  
Structural Mechanisms ◽  
Anxiety Depression ◽  
G Protein Coupled

The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABAB1 and GABAB2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.

scholarly journals HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: GPR101, an orphan GPCR with roles in growth and pituitary tumorigenesis

2020 ◽  
Vol 27 (8) ◽  
pp. T87-T97
Author(s):  
Giampaolo Trivellin ◽  
Fabio R Faucz ◽  
Adrian F Daly ◽  
Albert Beckers ◽  
Constantine A Stratakis
Keyword(s):  
Chromosome X ◽  
Endogenous Ligand ◽  
Guanine Nucleotide Binding Protein ◽  
Class A ◽  
Current State ◽  
Pituitary Tumorigenesis ◽  
Sporadic Cases ◽  
Guanine Nucleotide Binding ◽  
G Protein Coupled ◽  
Orphan Gpcr

We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated pituitary adenomas. X-LAG cases with early onset gigantism (in infants or toddlers) shared copy number gains (CNG) of the distal long arm of chromosome X (Xq26.3). In all patients described to date with Xq26.3 CNG and acro-gigantism, the only coding gene sequence shared by all chromosomal defects was that of GPR101. GPR101 is a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) with no known endogenous ligand. We review what is known about GPR101, specifically its expression profile in human and animal models, the evidence supporting causation of X-LAG and possibly other roles, including its function in growth, puberty and appetite regulation, as well as efforts to identify putative ligands.

scholarly journals Overcoming the Psychiatric Side Effects of the Cannabinoid CB1 Receptor Antagonists: Current Approaches for Therapeutics Development

2019 ◽  
Vol 19 (16) ◽  
pp. 1418-1435 ◽  
Author(s):  
Thuy Nguyen ◽  
Brian F. Thomas ◽  
Yanan Zhang
Keyword(s):  
Side Effects ◽  
Large Body ◽  
Cb1 Receptor ◽  
Allosteric Modulators ◽  
Cannabinoid Cb1 Receptor ◽  
Physiological Pathways ◽  
Treatment Of Obesity ◽  
Psychiatric Side Effects ◽  
Anxiety Depression ◽  
Cb1 Receptor Antagonists

The Cannabinoid CB1 Receptor (CB1R) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the CB1R in the last two decades.

Targeting the somatostatin receptors as a therapeutic approach for the preservation and protection of the mammalian cochlea from excitotoxicity

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Vesna Radojevic ◽  
Yves Brand ◽  
Soledad Levano ◽  
Cristian Setz ◽  
Daniel Bodmer
Keyword(s):  
Hair Cell ◽  
Cell Survival ◽  
Somatostatin Receptors ◽  
Organ Of Corti ◽  
Target Cells ◽  
Receptor Subtype ◽  
Knock Out ◽  
The Central Nervous System ◽  
And Function ◽  
G Protein Coupled

AbstractThe neuropeptide somatostatin (SST) is an important modulator of neurotransmission in the central nervous system (CNS) and binds to G-protein-coupled receptors (SSTR1-5) on target cells. Little is known about the expression and function of the somatostatinergic system in the mammalian cochlea. We analyzed the expression of SSTR1-SSTR5 in the immature mammalian cochlea. The peak in the expression of SSTR1 and SSTR2 at mRNA and protein level is around the onset of hearing to airborne sound, at postnatal day (P)14. This suggests their involvement in the maturation of the mammalian cochlea. We demonstrated that all five receptors are expressed in the inner hair cells (IHC) and outer hear cells (OHC) as well as in defined supporting cells of the organ of Corti (OC) in the adult mouse cochlea. A similar expression of the SSTRs in the IHC and OHC was found in cultivated P6 mouse OC explants as well as in neuroepithelial cell culture. In order to learn more about the regulation of SSTRs, we used mice with either a deletion of SSTR1, SSTR2 or SSTR1/SSTR2 double knock out (DKO). In DKO mice, SSTR5 was up-regulated and SSTR3 and SSTR4 were down regulated. These findings provide evidence of a compensatory regulation in the mammalian cochlea as a consequence of a receptor subtype deletion. In addition, we observed reduced levels of phospho-Akt and total-Akt in SSTR1 KO and DKO mice as compared to wild type (WT) mice. Akt is likely to be involved in hair cell survival. Most importantly, we found improved hair cell survival in somatostatin and octreotide treated OC explants that had been exposed to gentamicin compared to those explants exposed to gentamicin alone. These findings propose that the somatostatinergic system within the cochlea may have neuroprotective properties.

Sign in / Sign up

Export Citation Format

Share Document