scholarly journals Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity

2013 ◽  
Vol 9 ◽  
pp. 2916-2924 ◽  
Author(s):  
Thomas A Munro ◽  
Wei Xu ◽  
Douglas M Ho ◽  
Lee-Yuan Liu-Chen ◽  
Bruce M Cohen
Keyword(s):  
Furan Ring ◽  
Allosteric Modulation ◽  
Salvinorin A ◽  
Allosteric Modulators ◽  
Design Strategies ◽  
Binding Assays ◽  
Bivalent Ligand ◽  
Basic Nitrogen ◽  
Derivatives Of ◽  
Aspartate Residue

The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. Mutagenesis data suggest that salvinorin A (1) also binds to this allotopic pocket, adjacent to the aspartate residue that anchors the basic nitrogen atom of classical opiates (Asp138). It has been suggested that an H-bond donor appended to 1 might interact with Asp138, increasing affinity. Such a bivalent ligand might also possess altered functional selectivity. Based on modeling and known N-furanylmethyl opioid antagonists, we appended H-bond donors to the furan ring of 1. (Dimethylamino)methyl groups at C-15 or C-16 abolished affinity for κ-OR. Hydroxymethylation at C-16 was tolerated, but 15,16-bis-hydroxymethylation was not. Since allosteric modulators may go undetected in binding assays, we also tested these and other low-affinity derivatives of 1 for allosteric modulation of dynorphin A in the [35S]GTPγS assay. No modulation was detected. As an alternative attachment point for bivalent derivatives, we prepared the 2-(hydroxyethoxy)methyl ether, which retained high affinity for κ-OR. We discuss alternative design strategies for linked, fused or merged bivalent derivatives of 1.

scholarly journals Repositioning Dequalinium as Potent Muscarinic Allosteric Ligand by Combining Virtual Screening Campaigns and Experimental Binding Assays

2020 ◽  
Vol 21 (17) ◽  
pp. 5961
Author(s):  
Angelica Mazzolari ◽  
Silvia Gervasoni ◽  
Alessandro Pedretti ◽  
Laura Fumagalli ◽  
Rosanna Matucci ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Allosteric Modulation ◽  
Allosteric Modulators ◽  
Binding Assays ◽  
Docking Protocol ◽  
Consensus Models ◽  
Binding Cavity ◽  
Orthosteric Ligands ◽  
G Protein Coupled

Structure-based virtual screening is a truly productive repurposing approach provided that reliable target structures are available. Recent progresses in the structural resolution of the G-Protein Coupled Receptors (GPCRs) render these targets amenable for structure-based repurposing studies. Hence, the present study describes structure-based virtual screening campaigns with a view to repurposing known drugs as potential allosteric (and/or orthosteric) ligands for the hM2 muscarinic subtype which was indeed resolved in complex with an allosteric modulator thus allowing a precise identification of this binding cavity. First, a docking protocol was developed and optimized based on binding space concept and enrichment factor optimization algorithm (EFO) consensus approach by using a purposely collected database including known allosteric modulators. The so-developed consensus models were then utilized to virtually screen the DrugBank database. Based on the computational results, six promising molecules were selected and experimentally tested and four of them revealed interesting affinity data; in particular, dequalinium showed a very impressive allosteric modulation for hM2. Based on these results, a second campaign was focused on bis-cationic derivatives and allowed the identification of other two relevant hM2 ligands. Overall, the study enhances the understanding of the factors governing the hM2 allosteric modulation emphasizing the key role of ligand flexibility as well as of arrangement and delocalization of the positively charged moieties.

Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses

2020 ◽  
Vol 20 (31) ◽  
pp. 2852-2865 ◽  
Author(s):  
Damian Bartuzi ◽  
Tomasz M. Wróbel ◽  
Agnieszka A. Kaczor ◽  
Dariusz Matosiuk
Keyword(s):  
Side Effects ◽  
Opioid Receptors ◽  
Pain Perception ◽  
Allosteric Modulation ◽  
Allosteric Modulators ◽  
Signaling Mechanisms ◽  
Main Target ◽  
Allosteric Sites ◽  
Biased Signaling ◽  
Opioid Signaling

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is also presented.

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.

scholarly journals Research fronts of Chemical Biology

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shanshan Lv
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Chemical Biology ◽  
Rational Design ◽  
Future Research ◽  
Design Strategies ◽  
Binding Assays ◽  
Cellular Mechanisms ◽  
Diagnostic Technologies

Abstract Over the past decades, researchers have witnessed substantially increasing and ever-growing interests and efforts in Chemical Biology studies, thanks to the development of genome and epi-genome sequencing (revealing potential drug targets), synthetic chemistry (producing new medicines), bioorthogonal chemistry (chemistry in living systems) and high-throughput screening technologies (in vitro cell systems, protein binding assays and phenotypic assays). This report presents literature search results for current research in Chemical Biology, to explore basic principles, summarize recent advances, identify key challenges, and provide suggestions for future research (with a focus on Chemical Biology in the context of human health and diseases). Chemical Biology research can positively contribute to delivering a better understanding of the molecular and cellular mechanisms that accompany pathology underlying diseases, as well as developing improved methods for diagnosis, drug discovery, and therapeutic delivery. While much progress has been made, as shown in this report, there are still further needs and opportunities. For instance, pressing challenges still exist in selecting appropriate targets in biological systems and adopting more rational design strategies for the development of innovative and sustainable diagnostic technologies and medical treatments. Therefore, more than ever, researchers from different disciplines need to collaborate to address the challenges in Chemical Biology.

scholarly journals Widespread Changes in Positive Allosteric Modulation of the Muscarinic M1 Receptor in Some Participants With Schizophrenia

2019 ◽  
Vol 22 (10) ◽  
pp. 640-650 ◽  
Author(s):  
Shaun Hopper ◽  
Geoffrey Mark Pavey ◽  
Andrea Gogos ◽  
Brian Dean
Keyword(s):  
Carboxylic Acid ◽  
Radioligand Binding ◽  
Allosteric Modulation ◽  
Allosteric Modulator ◽  
Allosteric Modulators ◽  
Positive Allosteric Modulator ◽  
M1 Receptor ◽  
Area 6 ◽  
Subcortical Regions

Abstract Background Preclinical and some human data suggest allosteric modulation of the muscarinic M1 receptor (CHRM1) is a promising approach for the treatment of schizophrenia. However, it is suggested there is a subgroup of participants with schizophrenia who have profound loss of cortical CHRM1 (MRDS). This raises the possibility that some participants with schizophrenia may not respond optimally to CHRM1 allosteric modulation. Here we describe a novel methodology to measure positive allosteric modulation of CHRM1 in human CNS and the measurement of that response in the cortex, hippocampus, and striatum from participants with MRDS, non-MRDS and controls. Methods The cortex (Brodmann’s area 6), hippocampus, and striatum from 40 participants with schizophrenia (20 MRDS and 20 non-MRDS) and 20 controls were used to measure benzyl quinolone carboxylic acid-mediated shift in acetylcholine displacement of [3H]N-methylscopolamine using a novel in situ radioligand binding with autoradiography methodology. Results Compared with controls, participants with schizophrenia had lower levels of specific [3H]N-methylscopolamine binding in all CNS regions, whilst benzyl quinolone carboxylic acid-modulated binding was less in the striatum, Brodmann’s area 6, dentate gyrus, and subiculum. When divided by subgroup, only in MRDS was there lower specific [3H]N-methylscopolamine binding and less benzyl quinolone carboxylic acid-modulated binding in all cortical and subcortical regions studied. Conclusions In a subgroup of participants with schizophrenia, there is a widespread decreased responsiveness to a positive allosteric modulator at the CHRM1. This finding may have ramifications it positive allosteric modulators of the CHRM1 are used in clinical trials to treat schizophrenia as some participants may not have an optimal response.

Monofunctional Derivatives of Coproporphyrins for Phosphorescent Labeling of Proteins and Binding Assays

2001 ◽  
Vol 290 (2) ◽  
pp. 366-375 ◽  
Author(s):  
Tomás C. O'Riordan ◽  
Aleksi E. Soini ◽  
Dmitri B. Papkovsky
Keyword(s):  
Binding Assays ◽  
Derivatives Of

Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors, Part 1. N-(Phenylpropyl)-1-arylethylamines

2006 ◽  
Vol 59 (7) ◽  
pp. 445 ◽  
Author(s):  
David I. B. Kerr ◽  
Jennifer Ong ◽  
Michael V. Perkins ◽  
Rolf H. Prager ◽  
Ni Made Puspawati
Keyword(s):  
Biological Activity ◽  
Gabab Receptors ◽  
Allosteric Modulators ◽  
Positive Allosteric Modulators ◽  
Derivatives Of

A series of 15 analogues of fendiline, and 34 derivatives of N-(3-phenylpropyl)-1-arylethylamine have been prepared for evaluation as positive allosteric modulators of GABAB receptors. The most active (EC50, 10 nM) was N-(3,3-diphenylpropyl)-1-(3-chloro-4-methoxyphenyl)ethylamine 6g.

Thiosemicarbazone derivatives of nickel and copper: the unprecedented coordination of furan ring in octahedral nickel(ii) and of triphenylphosphine in three-coordinate copper(i) complexes

2011 ◽  
Vol 40 (13) ◽  
pp. 3219 ◽  
Author(s):  
Tarlok Singh Lobana ◽  
Poonam Kumari ◽  
Rekha Sharma ◽  
Alfonso Castineiras ◽  
Ray Jay Butcher ◽  
...  
Keyword(s):  
Furan Ring ◽  
Derivatives Of

Cycloadditions of C-benzoyl-N-phenylnitrone with furocondensed derivatives

1981 ◽  
Vol 46 (10) ◽  
pp. 2421-2427 ◽  
Author(s):  
Lubor Fišera ◽  
Miloslava Dandárová ◽  
Jaroslav Kováč ◽  
Peter Mesko ◽  
Alžbeta Krutošíková
Keyword(s):  
Transition State ◽  
Furan Ring ◽  
High Yield ◽  
Dipolar Cycloaddition ◽  
Orbital Interactions ◽  
Derivatives Of

Single regioisomeric cycloadduct IIa was formed in a 35% yield upon cycloaddition of the title nitrone Ia with benzofuran. The 1,3-dipolar cycloaddition proceeded with derivatives of 4-R-furo[3,2-b]pyrrole V or VI to the furan ring to form only one regioisomer VIIa or VIIIa in a high yield (93-95%). Dehydrogenation of the latter with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone led to the nitrone X or XII. Also C,N-diphenylnitrone reacted with furopyrroles to afford the cycloadduct VIIIb. Exclusively endo-cycloadducts originated; their transition state was stabilized by secondary orbital interactions.

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