Synthesis, binding assays, cytotoxic activity and docking studies of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor

2016 ◽  
Vol 124 ◽  
pp. 17-35 ◽  
Author(s):  
Javier Romero-Parra ◽  
Jaime Mella-Raipán ◽  
Vittoria Palmieri ◽  
Marco Allarà ◽  
Maria Jose Torres ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cannabinoid Receptor ◽  
Docking Studies ◽  
Binding Assays

scholarly journals Cannabis-Derived Compounds Cannabichromene and Δ9-Tetrahydrocannabinol Interact and Exhibit Cytotoxic Activity against Urothelial Cell Carcinoma Correlated with Inhibition of Cell Migration and Cytoskeleton Organization

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 465
Author(s):  
Omer Anis ◽  
Ajjampura C. Vinayaka ◽  
Nurit Shalev ◽  
Dvora Namdar ◽  
Stalin Nadarajan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Migration ◽  
Cytotoxic Activity ◽  
Cell Lines ◽  
High Performance ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Quantitative Polymerase Chain Reaction ◽  
Migration And Invasion ◽  
Xtt Assay

Cannabis sativa contains more than 500 constituents, yet the anticancer properties of the vast majority of cannabis compounds remains unknown. We aimed to identify cannabis compounds and their combinations presenting cytotoxicity against bladder urothelial carcinoma (UC), the most common urinary system cancer. An XTT assay was used to determine cytotoxic activity of C. sativa extracts on T24 and HBT-9 cell lines. Extract chemical content was identified by high-performance liquid chromatography (HPLC). Fluorescence-activated cell sorting (FACS) was used to determine apoptosis and cell cycle, using stained F-actin and nuclei. Scratch and transwell assays were used to determine cell migration and invasion, respectively. Gene expression was determined by quantitative Polymerase chain reaction (PCR). The most active decarboxylated extract fraction (F7) of high-cannabidiol (CBD) C. sativa was found to contain cannabichromene (CBC) and Δ9-tetrahydrocannabinol (THC). Synergistic interaction was demonstrated between CBC + THC whereas cannabinoid receptor (CB) type 1 and type 2 inverse agonists reduced cytotoxic activity. Treatments with CBC + THC or CBD led to cell cycle arrest and cell apoptosis. CBC + THC or CBD treatments inhibited cell migration and affected F-actin integrity. Identification of active plant ingredients (API) from cannabis that induce apoptosis and affect cell migration in UC cell lines forms a basis for pre-clinical trials for UC treatment.

scholarly journals New Pyridone-Based Derivatives as Cannabinoid Receptor Type 2 Agonists

2021 ◽  
Vol 22 (20) ◽  
pp. 11212
Author(s):  
Manuel Faúndez-Parraguez ◽  
Carlos Alarcón-Miranda ◽  
Young Hwa Cho ◽  
Hernán Pessoa-Mahana ◽  
Carlos Gallardo-Garrido ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Docking Studies ◽  
Receptor Type ◽  
Intracellular Camp ◽  
Type I ◽  
Type Ii ◽  
New Information ◽  
Starting Point ◽  
Inflammatory Processes

The activation of the human cannabinoid receptor type II (CB2R) is known to mediate analgesic and anti-inflammatory processes without the central adverse effects related to cannabinoid receptor type I (CB1R). In this work we describe the synthesis and evaluation of a novel series of N-aryl-2-pyridone-3-carboxamide derivatives tested as human cannabinoid receptor type II (CB2R) agonists. Different cycloalkanes linked to the N-aryl pyridone by an amide group displayed CB2R agonist activity as determined by intracellular [cAMP] levels. The most promising compound 8d exhibited a non-toxic profile and similar potency (EC50 = 112 nM) to endogenous agonists Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) providing new information for the development of small molecules activating CB2R. Molecular docking studies showed a binding pose consistent with two structurally different agonists WIN-55212-2 and AM12033 and suggested structural requirements on the pyridone substituents that can satisfy the orthosteric pocket and induce an agonist response. Our results provide additional evidence to support the 2-pyridone ring as a suitable scaffold for the design of CB2R agonists and represent a starting point for further optimization and development of novel compounds for the treatment of pain and inflammation.

scholarly journals Synthesis and Biological Screening of New Thiadiazolopyrimidine-based Polycyclic Compounds

2021 ◽  
Author(s):  
Alaa M. Alqahtani
Keyword(s):  
Cytotoxic Activity ◽  
Fibroblast Cell ◽  
Docking Studies ◽  
Normal Fibroblast ◽  
Polycyclic Compounds ◽  
Gram Positive Bacteria ◽  
Standard Normal ◽  
Structural Activity Relationship ◽  
Cyclic Compounds ◽  
Mcf 7

Abstract New tri- and tetra-cyclic compounds based on the thiadiazolopyrimidine ring system were prepared and their antimicrobial activity were estimated. The achieved results evidenced that pyrano-thiadiazolopyrimidine compounds 8a-b and 9a-b have substantial efficiencies toward the two strains of Gram-positive bacteria (S. aureus and B. cereus). While tetracyclic derivatives pyrazolopyrimido-thiadiazolopyrimidine derivatives 16a-b and 17a-b displayed prominent efficiencies toward the two strains of Gram-negative bacteria (E. coli and P. aeruginosa). In addition, compounds 8a-b and 9a-b presented good efficacy toward C. albicans. The activity of antiquorum-sensing (anti-QS) inhibition of the new synthesized thiadiazolopyrimidine-based compounds was tested toward C. violaceum, where derivatives 16a-b, 17a-b, 8b and 9a displayed satisfactory activity. Cytotoxic activity of the same derivatives was screened toward various cancer cell lines (MCF-7, PC3, Hep-2 and HepG2) and standard normal fibroblast cell (WI38) by utilizing the MTT assay. The pyrazolopyrimido-thiadiazolopyrimidine derivatives 16a, 16b, 17a and 17b recorded potent cytotoxic efficacy against MCF-7 cells with IC50 values ranging from 5.69 to 9.36 µM. Also, the endorsed structural activity relationship (SAR) for the inspected thiadiazolopyrimidine derivatives provided an awareness concerning the chemical structure connected to anticancer efficiency. In silico docking studies were implemented toward silence hormone signaling in breast (PDB Code-5NQR). The results are consistent and supportive to the cytotoxic activity.

scholarly journals Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3808
Author(s):  
Juan Pablo González-Gutiérrez ◽  
Hernán Armando Pessoa-Mahana ◽  
Patricio Ernesto Iturriaga-Vásquez ◽  
Miguel Iván Reyes-Parada ◽  
Nicolas Esteban Guerra-Díaz ◽  
...  
Keyword(s):  
Binding Site ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Docking Studies ◽  
Binding Assays ◽  
Serotonin Transporters ◽  
Paroxetine Binding ◽  
Compound 21 ◽  
Binding Percentage

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4β2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 μM for h-DAT and 0.031 ± 0.006 μM for α4β2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 μM for α4β2 nAChR and 0.075 ± 0.009 μM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4β2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/β2 subunit interfaces of α4β2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.

scholarly journals Computer modeling of Cannabinoid receptor type 1

2018 ◽  
Vol 16 ◽  
pp. 02008
Author(s):  
Fatima Sapundzhi ◽  
Tatyana Dzimbova ◽  
Nevena Pencheva ◽  
Peter Milanov
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Scoring Function ◽  
Docking Studies ◽  
Cb1 Receptors ◽  
Important Class ◽  
Pain Sensation ◽  
Physiological Processes ◽  
Selective Ligands

Cannabinoid receptors are important class of receptors as they are involved in various physiological processes such as appetite, pain-sensation, mood, and memory. It is important to design receptor-selective ligands in order to treat a particular disorder. The aim of the present study is to model the structure of cannabinoid receptor CB1 and to perform docking between obtained models and known ligands. Two models of CBR1 were prepared with two different methods (Modeller of Chimera and MOE). They were used for docking with GOLD 5.2. It was established a high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD, which concerns both models. This suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.

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 Anti-proliferative Activity of Some Oleanolic Acid Derivatives with Potent Topoisomerase Inhibitory Activity on B16 Melanoma Cells

2020 ◽  
Vol 9 (1) ◽  
pp. 26-28
Author(s):  
Ahmed Ashour ◽  
Ryuichiro Kondo ◽  
Kuniyoshi Shimizu
Keyword(s):  
Cytotoxic Activity ◽  
Oleanolic Acid ◽  
Anticancer Agents ◽  
Inhibitory Activity ◽  
Topoisomerase I ◽  
Melanoma Cells ◽  
Docking Studies ◽  
B16 Melanoma ◽  
Melanoma Cancer ◽  
B16 Melanoma Cells

Our previous study included the semisynthetic reactions on oleanolic acid, a common wood-derived oleanane-type triterpene. Ten rationally designed derivatives of oleanolic acid were synthesized based on docking studies and tested for their topoisomerase I and IIα inhibitory activity. Semisynthetic reactions targeted C-3, C-12, C-13 and C-17. Some of these compounds act as dual inhibitors for both topoisomerase I and IIα giving new anticancer agents. The cytotoxic activity of these compounds on B16 melanoma cancer cells was evaluated. Results showed that most of these compounds have a higher cytotoxic activity on B16 melanoma cells.

scholarly journals Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3β of new indirubin-3ʹ-oxime derivatives

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nguyen Trong Dan ◽  
Hoang Duc Quang ◽  
Vuong Van Truong ◽  
Do Huu Nghi ◽  
Nguyen Manh Cuong ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Docking Studies ◽  
Design Synthesis ◽  
Activity Evaluation ◽  
Oxime Derivatives ◽  
Gsk 3Β ◽  
Target Enzyme

scholarly journals Discovery of Orexant and Anorexant Agents with Indazole Scaffold Endowed with Peripheral Antiedema Activity

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 492 ◽  
Author(s):  
Dimmito ◽  
Stefanucci ◽  
Pieretti ◽  
Minosi ◽  
Dvorácskó ◽  
...  
Keyword(s):  
Feeding Behavior ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Methyl Esters ◽  
Endocannabinoid System ◽  
Tail Flick ◽  
Binding Assays ◽  
Tail Flick Test

The endocannabinoid system represents an integrated neuronal network involved in the control of several organisms’ functions, such as feeding behavior. A series of hybrids of 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (mimonabant), a well-known inverse agonist of the type-1 cannabinoid receptor (CB1), once used as an antiobesity drug, and the N-(2S)-substitutes of 1-[(4-fluorophenyl)methyl]indazole-3-carboxamide with 1-amino-3-methyl-1-oxobutane (AB-Fubinaca), 1-amino-3,3-dimethyl-1-oxobutane (ADB-Fubinaca), and 3-methylbutanoate (AMB-Fubinaca), endowed with potent agonistic activity towards cannabinoid receptors CB1 and CB2 were in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied by binding assays to cannabinoid receptors and by functional receptor assays, using rat brain membranes in vitro. The most active among them as an agonist, (S)-1-(2,4-dichlorobenzyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-1H-indazole-3-carboxamide (LONI11), and an antagonist, (S)-2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoic acid (LONI4), were tested in vivo in mic, to evaluate their ability to stimulate or suppress feeding behavior after intraperitoneal (i.p.) administration. For a LONI11 formalin test and a tail flick test after an administration by the subcutaneous (s.c.) and intracerebroventricular (i.c.v.) routes, respectively, were also carried out in vivo in mice to investigate the antinociceptive property at the central and peripheral levesl. We observed a significant orexant effect for LONI11 and an intense anorexant effect for (S)-methyl 2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (LONI2) and LONI4. In zymosan-induced edema and hyperalgesia, LONI11 reduced the percent of paw volume increase and paw latency after s.c. administration, also suggesting a possible peripheral anti-inflammatory activity.

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