Small Molecule Neuropeptide S and Melanocortin 4 Receptor Ligands as Potential Treatments for Substance Use Disorders

Blough, Bruce E.; Namjoshi, Ojas A.

doi:10.1007/164_2019_313

Cited by 5 publications

(4 citation statements)

References 108 publications

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“…The choice of these receptors is due to rather extensive information about their allosteric sites and the diversity of their endogenous and synthetic allosteric regulators, including autoantibodies and synthetic pepducins. At the same time, for a number of other GPCRs, there is also a lot of data on allosteric regulation and their analysis is presented in a number of recent comprehensive reviews and analytical articles: for muscarinic acetylcholine receptors [ 171 , 172 , 173 , 174 ], for metabotropic glutamate receptors [ 171 , 175 , 176 ], for 5-hydroxytryptamine (serotonin) receptors [ 177 , 178 ], for dopamine receptors [ 177 , 179 ], for opioid receptors [ 178 , 180 , 181 ], for cannabinoid receptors [ 176 , 182 , 183 , 184 ], for adenosine receptors [ 185 ], for neuropeptide Y receptors [ 186 ], for melanocortin receptors [ 186 ], for angiotensin receptors [ 187 ], for glucagon-like peptide-1 receptors [ 176 , 188 ], and for free fatty acid receptors [ 58 ].…”

Section: Allosteric Sites In Different Families Of Gpcrsmentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

2023

IJMS

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Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

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Section: Allosteric Sites In Different Families Of Gpcrsmentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

2023

IJMS

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“…The choice of these receptors is due to rather extensive information about their allosteric sites and the diversity of their endogenous and synthetic allosteric regulators, including autoantibodies and synthetic pepducins. At the same time, for a number of other GPCRs, there is also a lot of data on allosteric regulation and their analysis is presented in a number of recent comprehensive reviews and analytical articles: for muscarinic acetylcholine receptors [162][163][164][165], for metabotropic glutamate receptors [162,166,167], for 5-hydroxytryptamine (serotonine) receptors [168,169], for dopamine receptors [168,170], for opioid receptors [169,171,172], for cannabinoid receptors [167,[173][174][175], for adenosine receptors [176], for neuropeptide Y receptors [177], for melanocortin receptors [177], for angiotensin receptors [178], for glucagon-like peptide-1 receptors [167,179], and for free fatty acid receptors [50].…”

Section: Gpcr-complexes and Allosteric Regulationmentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Ao¹

2023

Preprint

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A separate group consists of compounds that are able to simultaneously interact with both orthosteric and allosteric sites, which are classified as bitopic GPCR ligands [74, 76-81]. They have two pharmacophores, one of which binds with high affinity to the orthosteric site, while the other, with lower affinity, binds to the allosteric site. If these sites are spatially separated in the receptor, then the pharmacophores in the bitopic ligand must be connected with a flexible linker, the length of which exactly corresponds to the distance between the orthosteric and allosteric sites. At the same time, it is important that the linker does not significantly affect the conformational rearrangements in the receptor caused by its activation by orthosteric and (or) allosteric agonists [74, 79].

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“…On the contrary, NPSR is widely expressed in several brain regions (i.e., hypothalamus, endopiriform nucleus, amygdala, subiculum, cortex, and nuclei of the thalamic midline). , In vivo , NPS has been shown to control several biological functions in rodents including stress, anxiety, social behavior, locomotor activity, wakefulness, food intake and gastrointestinal functions, memory processes, pain, and drug abuse. , As far as the therapeutic potential of selective NPSR ligands is concerned, NPSR agonists may be useful as innovative anxiolytics devoid of sedative effects, analgesics, and nootropics. On the other hand, NPSR antagonists may be useful to treat substance abuse disorders against which there is an urgent need for the exploration of novel potential drug targets and for developing innovative therapeutic approaches …”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, NPSR antagonists may be useful to treat substance abuse disorders against which there is an urgent need for the exploration of novel potential drug targets and for developing innovative therapeutic approaches. 8 NPSR antagonists with potent in vitro activity have been developed in the last few years and a few compounds are currently in use as pharmacological tools. 7 Among these, oxazolo [3,4-a]pyrazine derivatives have been first reported in 2005 by Takeda Pharmaceuticals, 9 and SHA-68 (1, Figure 1) is the most representative member of this class.…”

Section: ■ Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies on Oxazolo[3,4-a]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent In Vivo Activity

et al. 2021

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Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists in vitro have been discovered which, however, require further optimization of their in vivo pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4- a ]pyrazine class. The guanidine derivative 16 exhibited nanomolar activity in vitro and 5-fold improved potency in vivo compared to SHA-68 , a reference pharmacological tool in this field. Compound 16 can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure–activity relationships and provide an updated model of ligand/NPSR interactions.

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Small Molecule Neuropeptide S and Melanocortin 4 Receptor Ligands as Potential Treatments for Substance Use Disorders

Cited by 5 publications

References 108 publications

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Structure–Activity Relationship Studies on Oxazolo[3,4-a]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent In Vivo Activity

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