Rotenoids and Other Specialized Metabolites from the Roots of Mirabilis multiflora: Opioid and Cannabinoid Receptor Radioligand Binding Affinities

2021 ◽  
Vol 84 (4) ◽  
pp. 1392-1396
Author(s):  
Vimal K. Sharma ◽  
Radhakrishnan Srivedavyasasri ◽  
Zulfiqar Ali ◽  
Jordan K. Zjawiony ◽  
Samir A. Ross ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Radioligand Binding ◽  
Binding Affinities ◽  
Specialized Metabolites

scholarly journals Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 KATP channels

2012 ◽  
Vol 302 (5) ◽  
pp. E540-E551 ◽  
Author(s):  
Christopher J. Lynch ◽  
Qing Zhou ◽  
Show-Ling Shyng ◽  
David J. Heal ◽  
Sharon C. Cheetham ◽  
...  
Keyword(s):  
Chronic Treatment ◽  
Cannabinoid Receptor ◽  
Radioligand Binding ◽  
In Vitro Studies ◽  
Zucker Rats ◽  
K Channel ◽  
Inverse Agonists ◽  
Chronic Effects

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg−1·day−1) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1-mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 KATP KCOs where rimonabant and ibipinabant allosterically regulated 3H-glibenclamide-specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 KATP channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.

Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB1

2013 ◽  
Vol 87 (7) ◽  
pp. 1287-1297 ◽  
Author(s):  
Verena J. Koller ◽  
Gerhard J. Zlabinger ◽  
Volker Auwärter ◽  
Sabine Fuchs ◽  
Siegfried Knasmueller
Keyword(s):  
Cannabinoid Receptor ◽  
Synthetic Cannabinoids ◽  
Receptor Subtype ◽  
Binding Affinities ◽  
High Binding

scholarly journals Benzyl-1,2,4-triazoles as CB1 Cannabinoid Receptor Ligands: Preparation and In Vitro Pharmacological Evaluation

2016 ◽  
Vol 2016 ◽  
pp. 1-9
Author(s):  
Laura Hernandez-Folgado ◽  
Juan Decara ◽  
Fernando Rodríguez de Fonseca ◽  
Pilar Goya ◽  
Nadine Jagerovic
Keyword(s):  
Cannabinoid Receptor ◽  
Radioligand Binding ◽  
Pharmacological Properties ◽  
Binding Assays ◽  
Receptor Ligands ◽  
Cannabinoid Type 1 Receptor ◽  
Cb1 Cannabinoid Receptor ◽  
Nanomolar Range

In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type 1 receptor (CB1R) antagonists. In order to expand the number of cannabinoid ligands with a central 1,2,4-triazole scaffold, we have synthesized a novel series of 1-benzyl-1H-1,2,4-triazoles, and some of them were evaluated by CB1R radioligand binding assays. Compound 12a showed the most interesting pharmacological properties, possessing a CB1R affinity in the nanomolar range.

scholarly journals Erratum to: Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB1

2013 ◽  
Vol 87 (7) ◽  
pp. 1299-1299
Author(s):  
Verena J. Koller ◽  
Gerhard J. Zlabinger ◽  
Volker Auwärter ◽  
Sabine Fuchs ◽  
Siegfried Knasmueller
Keyword(s):  
Cannabinoid Receptor ◽  
Synthetic Cannabinoids ◽  
Receptor Subtype ◽  
Binding Affinities ◽  
High Binding

scholarly journals A Theoretical Study of the Relationships between Electronic Structure and CB1 and CB2 Cannabinoid Receptor Binding Affinity in a Group of 1-Aryl-5-(1-H-pyrrol-1-yl)-1-H-pyrazole-3-carboxamides

2014 ◽  
Vol 2014 ◽  
pp. 1-15
Author(s):  
Francisco Salgado-Valdés ◽  
Juan S. Gómez-Jeria
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Theoretical Study ◽  
Cannabinoid Receptor ◽  
Geometry Optimization ◽  
Wave Functions ◽  
Binding Affinities ◽  
Full Geometry Optimization ◽  
Receptor Binding Affinity ◽  
Reactivity Indices

We report the results of a search for model-based relationships between hCB1 and hCB2 receptor binding affinity and molecular structure for a group of 1-aryl-5-(1-H-pyrrol-1-yl)-1-H-pyrazole-3-carboxamides. The wave functions and local atomic reactivity indices were obtained at the B3LYP/6-31G(d,p) levels of theory with full geometry optimization. Interaction pharmacophores were generated for both receptors. The main conclusions of this work are as follows. (1) We obtained statistically significant equations relating the variation of hCB1 and hCB2 receptor binding affinities with the variation of definite sets of local atomic reactivity indices. (2) The interaction of the molecules with the hCB1 and hCB2 receptors seems to be highly complex and mainly orbital controlled. (3) The interaction mechanisms seem to be different for each type of receptor. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process.

scholarly journals Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands

2021 ◽  
Vol 22 (5) ◽  
pp. 2329
Author(s):  
Marek Król ◽  
Grzegorz Ślifirski ◽  
Jerzy Kleps ◽  
Szymon Ulenberg ◽  
Mariusz Belka ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
13C Nmr Spectroscopy ◽  
Binding Affinities ◽  
Binding Assays ◽  
Transporter Protein ◽  
Chemical Structures ◽  
Serotonin Transporter Protein ◽  
Very High

Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d.

scholarly journals Cannabis Constituents and Acetylcholinesterase Interaction: Molecular Docking, In Vitro Studies and Association with CNR1 rs806368 and ACHE rs17228602

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 758
Author(s):  
Tiyyaba Furqan ◽  
Sidra Batool ◽  
Rabia Habib ◽  
Mamoona Shah ◽  
Huba Kalasz ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cannabinoid Receptor ◽  
Human Subjects ◽  
Inhibitory Effect ◽  
Ache Inhibitor ◽  
Binding Affinities ◽  
Cannabinoid Receptor 1 ◽  
Inhibitory Potential

The study documented here was aimed to find the molecular interactions of some of the cannabinoid constituents of cannabis with acetylcholinesterase (AChE). Molecular docking and LogP determination were performed to predict the AChE inhibitory effect and lipophilicity. AChE enzyme activity was measured in the blood of cannabis addicted human subjects. Further, genetic predisposition to cannabis addiction was investigated by association analysis of cannabinoid receptor 1 (CNR1) single nucleotide polymorphism (SNP) rs806368 and ACHE rs17228602 using restriction fragment length polymorphism (RFLP) method. All the understudied cannabis constituents showed promising binding affinities with AChE and are lipophilic in nature. The AChE activity was observed to be indifferent in cannabis addicted and non-addicted healthy controls. There was no significant association with CNR1 SNP rs806368 and ACHE rs17228602. The study concludes that in silico prediction for individual biomolecules of cannabis is different from in vivo physiological action in human subjects when all are present together. However, for a deeper mechanistic insight into these interactions and association, multi-population studies are suggested. Further studies to explore the inhibitory potential of different cannabis constituents for intended AChE inhibitor-based drug are warranted.

Pharmacological Characterization of Receptor Redistribution and β-Arrestin Recruitment Assays for the Cannabinoid Receptor 1

2009 ◽  
Vol 14 (7) ◽  
pp. 811-823 ◽  
Author(s):  
Miranda M.C. van der Lee ◽  
Marion Blomenröhr ◽  
Antoon A. van der Doelen ◽  
Jesse W.Y. Wat ◽  
Niels Smits ◽  
...  
Keyword(s):  
G Protein ◽  
Cannabinoid Receptor ◽  
Receptor Activation ◽  
Binding Affinities ◽  
Cannabinoid Receptor 1 ◽  
Pharmacological Characterization ◽  
Cellular Effects ◽  
Partial Agonists ◽  
C Terminus ◽  
G Protein Coupled

Receptor redistribution and β-arrestin recruitment assays provide a G-protein-subtype-independent method to measure ligand-stimulated activation of G-protein-coupled receptors. In particular β-arrestin assays are becoming an increasingly popular tool for drug discovery. The authors have compared a high-content-imaging-based Redistribution® assay and 2 nonimaging-based β-arrestin recruitment assays, Tango™ and PathHunter ™, for the cannabinoid receptor 1. Inasmuch as all 3 assays use receptors that are modified at the C-terminus, the authors verified their pharmacology via detection of Gαi coupling of the receptor in cAMP assays using reference ligands. The potencies and efficacies of the cannabinoid receptor agonists CP55,940 and WIN55,212-2 correlated well between the 3 assays, and are comparable with the measured ligand binding affinities. The inverse agonist SR141716 decreased basal signal in all 3 assays, but only in the Tango bla assay a reliable EC50 could be determined for this compound, suggesting that Tango is the most suitable assay for the identification of new inverse agonists. Both the Redistribution and the PathHunter assay could discriminate partial agonists from full agonists, whereas in the Tango assay partial agonists behaved as full agonists. Only the PathHunter cells allowed detection of cannabinoid receptor activation via β-arrestin recruitment and Gαi-protein-mediated inhibition of cAMP, thus enabling the identification of biased ligands that differ in these cellular effects. The characteristics and limitations of the different assays are discussed. ( Journal of Biomolecular Screening 2009:811-823)

scholarly journals Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6679
Author(s):  
Mukuo Wang ◽  
Shujing Hou ◽  
Ye Liu ◽  
Dongmei Li ◽  
Jianping Lin
Keyword(s):  
Virtual Screening ◽  
Cannabinoid Receptor ◽  
Radioligand Binding ◽  
Endocannabinoid System ◽  
Screening Strategy ◽  
Antagonistic Activity ◽  
Cb2 Receptor ◽  
Binding Assays ◽  
Cannabinoid Receptor 2 ◽  
Functional Assays

The endocannabinoid system plays an essential role in the regulation of analgesia and human immunity, and Cannabinoid Receptor 2 (CB2) has been proved to be an ideal target for the treatment of liver diseases and some cancers. In this study, we identified CB2 antagonists using a three-step “deep learning–pharmacophore–molecular docking” virtual screening approach. From the ChemDiv database (1,178,506 compounds), 15 hits were selected and tested by radioligand binding assays and cAMP functional assays. A total of 7 out of the 15 hits were found to exhibit binding affinities in the radioligand binding assays against CB2 receptor, with a pKi of 5.15-6.66, among which five compounds showed antagonistic activities with pIC50 of 5.25–6.93 in the cAMP functional assays. Among these hits, Compound 8 with the 4H-pyrido[1,2-a]pyrimidin-4-one scaffold showed the best binding affinity and antagonistic activity with a pKi of 6.66 and pIC50 of 6.93, respectively. The new scaffold could serve as a lead for further development of CB2 drugs. Additionally, we hope that the model in this study could be further utilized to identify more novel CB2 receptor antagonists, and the developed approach could also be used to design potent ligands for other therapeutic targets.

Specificity determinants of phosphoprotein phosphatases controlling kinetochore functions

2020 ◽  
Vol 64 (2) ◽  
pp. 325-336 ◽  
Author(s):  
Dimitriya H. Garvanska ◽  
Jakob Nilsson
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Activity Level ◽  
Phosphorylation Sites ◽  
Binding Affinities ◽  
Mitotic Kinases ◽  
Anaphase Onset ◽  
Phosphoprotein Phosphatases ◽  
Linear Motifs ◽  
Temporal And Spatial ◽  
Kinetochore Function

Abstract Kinetochores are instrumental for accurate chromosome segregation by binding to microtubules in order to move chromosomes and by delaying anaphase onset through the spindle assembly checkpoint (SAC). Dynamic phosphorylation of kinetochore components is key to control these activities and is tightly regulated by temporal and spatial recruitment of kinases and phosphoprotein phosphatases (PPPs). Here we focus on PP1, PP2A-B56 and PP2A-B55, three PPPs that are important regulators of mitosis. Despite the fact that these PPPs share a very similar active site, they target unique ser/thr phosphorylation sites to control kinetochore function. Specificity is in part achieved by PPPs binding to short linear motifs (SLiMs) that guide their substrate specificity. SLiMs bind to conserved pockets on PPPs and are degenerate in nature, giving rise to a range of binding affinities. These SLiMs control the assembly of numerous substrate specifying complexes and their position and binding strength allow PPPs to target specific phosphorylation sites. In addition, the activity of PPPs is regulated by mitotic kinases and inhibitors, either directly at the activity level or through affecting PPP–SLiM interactions. Here, we discuss recent progress in understanding the regulation of PPP specificity and activity and how this controls kinetochore biology.

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