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 N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo

2000 ◽  
Vol 351 (3) ◽  
pp. 817 ◽  
Author(s):  
Tiziana BISOGNO ◽  
Dominique MELCK ◽  
Mikhail Yu. BOBROV ◽  
Natalia M. GRETSKAYA ◽  
Vladimir V. BEZUGLOV ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Receptor Ligands ◽  
Cb1 Cannabinoid Receptor

Design, synthesis and biological evaluation of piperazine analogues as CB1 cannabinoid receptor ligands

2008 ◽  
Vol 16 (7) ◽  
pp. 4035-4051 ◽  
Author(s):  
Kwang-Seop Song ◽  
Sung-Han Lee ◽  
Hyun Ji Chun ◽  
Jong Yup Kim ◽  
Myung Eun Jung ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Biological Evaluation ◽  
Receptor Ligands ◽  
Design Synthesis ◽  
Cb1 Cannabinoid Receptor ◽  
Synthesis And Biological Evaluation

scholarly journals GPR18, GPR55 and GPR119 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Stephen P.H. Alexander ◽  
Andrew J. Irving
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Structural Similarity ◽  
Synthetic Cannabinoid ◽  
Receptor Ligands ◽  
Orphan Status ◽  
Endogenous Cannabinoid

GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [98]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.

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.

CB1 Cannabinoid Receptor Ligands

2005 ◽  
Vol 5 (7) ◽  
pp. 631-640 ◽  
Author(s):  
Ganesh Thakur ◽  
Spyros Nikas ◽  
Alexandros Makriyannis
Keyword(s):  
Cannabinoid Receptor ◽  
Receptor Ligands ◽  
Cb1 Cannabinoid Receptor

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.

scholarly journals Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Frank Herrmann ◽  
Manuela Hessmann ◽  
Sabine Schaertl ◽  
Karola Berg-Rosseburg ◽  
Christopher J Brown ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Trinucleotide Repeat ◽  
Radioligand Binding ◽  
Ex Vivo ◽  
Binding Assays ◽  
Pharmacological Characterization ◽  
Binding Characteristics

AbstractHuntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer’s disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer’s disease patients.

scholarly journals Role of Major Endocannabinoid-Binding Receptors during Mouse Oocyte Maturation

2019 ◽  
Vol 20 (12) ◽  
pp. 2866 ◽  
Author(s):  
Sandra Cecconi ◽  
Gianna Rossi ◽  
Sergio Oddi ◽  
Valentina Di Nisio ◽  
Mauro Maccarrone
Keyword(s):  
Transient Receptor Potential ◽  
Cannabinoid Receptor ◽  
Polar Body ◽  
Germinal Vesicle ◽  
Receptor Potential ◽  
Confocal Imaging ◽  
Transient Receptor Potential Vanilloid

Endocannabinoids are key-players of female fertility and potential biomarkers of reproductive dysfunctions. Here, we investigated localization and expression of cannabinoid receptor type-1 and -2 (CB1R and CB2R), G-protein coupled receptor 55 (GPR55), and transient receptor potential vanilloid type 1 channel (TRPV1) in mouse oocytes collected at different stages of in vivo meiotic maturation (germinal vesicle, GV; metaphase I, MI; metaphase II, MII) through qPCR, confocal imaging, and western blot. Despite the significant decrease in CB1R, CB2R, and GPR55 mRNAs occurring from GV to MII, CB2R and GPR55 protein contents increased during the same period. At GV, only CB1R was localized in oolemma, but it completely disappeared at MI. TRPV1 was always undetectable. When oocytes were in vitro matured with CB1R and CB2R but not GPR55 antagonists, a significant delay of GV breakdown occurred, sustained by elevated intraoocyte cAMP concentration. Although CBRs antagonists did not affect polar body I emission or chromosome alignment, GPR55 antagonist impaired in ~75% of oocytes the formation of normal-sized MI and MII spindles. These findings open a new avenue to interrogate oocyte pathophysiology and offer potentially new targets for the therapy of reproductive alterations.

scholarly journals In vitro and in vivo pharmacology of synthetic olivetol- or resorcinol-derived cannabinoid receptor ligands

2006 ◽  
Vol 149 (4) ◽  
pp. 431-440 ◽  
Author(s):  
M G Cascio ◽  
T Bisogno ◽  
E Palazzo ◽  
A Thomas ◽  
M van der Stelt ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Receptor Ligands
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