Probing the Interaction of SR141716A with the CB1 Receptor

Shim, Joong‐Youn; Bertalovitz, Alexander C.; Kendall, Debra A.

doi:10.1074/jbc.m112.390955

Cited by 17 publications

(27 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with the proposed model, substituents at position 5 would extend toward the hydrophobic channel described below (see TAMRA positioning). Recently, a binding mode of Rimonabant which is rotated of 90° with respect to ours, facing the 5 position of the pyrazole ring towards the TM 5, was reported40. Such a difference is likely due to the different template used to build the CB 1 model (human β 2 -adrenergic)40.…”

Section: Resultsmentioning

confidence: 80%

Beyond radio-displacement techniques for Identification of CB1 Ligands: The First Application of a Fluorescence-quenching Assay

Bruno

Lembo

Novellino

et al. 2014

Sci Rep

View full text Add to dashboard Cite

Cannabinoid type 1 Receptor (CB1) belongs to the GPCR family and it has been targeted, so far, for the discovery of drugs aimed at the treatment of neuropathic pain, nausea, vomit, and food intake disorders. Here, we present the development of the first fluorescent assay enabling the measurement of kinetic binding constants for CB1orthosteric ligands. The assay is based on the use of T1117, a fluorescent analogue of AM251. We prove that T1117 binds endogenous and recombinant CB1 receptors with nanomolar affinity. Moreover, T1117 binding to CB1 is sensitive to the allosteric ligand ORG27569 and thus it is applicable to the discovery of new allosteric drugs. The herein presented assay constitutes a sustainable valid alternative to the expensive and environmental impacting radiodisplacement techniques and paves the way for an easy, fast and cheap high-throughput drug screening toward CB1 for identification of new orthosteric and allosteric modulators.

show abstract

Section: Resultsmentioning

confidence: 80%

Beyond radio-displacement techniques for Identification of CB1 Ligands: The First Application of a Fluorescence-quenching Assay

Bruno

Lembo

Novellino

et al. 2014

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Earlier models have been proposed based on the structures of bovine rhodopsin (Hurst et al, 2002;McAllister et al, 2003;Shim et al, 2003;Salo et al, 2004;Silvestri et al, 2008) or the b2-adrenergic receptor (Shim et al, 2012). The more recent structure used here as template affords a sequence alignment that is almost devoid of insertions and deletions.…”

Section: Resultsmentioning

confidence: 99%

Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists

et al. 2015

View full text Add to dashboard Cite

6-Alkoxy-5-aryl-3-pyridincarboxamides, including the brain-, have been recently introduced as selective, high-affinity antagonists of the human cannabinoid-1 receptor (hCB 1 R). Binding analyses revealed two orders of magnitude lower affinity of these compounds for mouse and rat versus human CB 1 R, whereas the affinity of rimonabant is comparable for all three CB 1 Rs. Modeling of ligand binding to CB 1 R and binding assays with native and mutant (Ile105Met) hCB 1 Rs indicate that the Ile105 to Met mutation in rodent CB 1 Rs accounts for the species-dependent affinity of 14g and 14h. Our work identifies Ile105 as a new pharmacophore component for developing better hCB 1 R antagonists and invalidates rodent models for assessing the antiobesity efficacy of 14g and 14h.

show abstract

“…The hydrogen bonding interaction is consistent with our prior CB 1 mutant cycle studies, which indicated that the amide oxygen of SR141716A interacts directly with K3.28 192 . This interaction is critical for the inverse agonist properties of SR141716A (Hurst et al, , 2006 (Shim et al, 2012). Figure 4, B and D illustrates the final docked conformation of LDK1229 (shown in lavender) in the CB 1 inactive state model (Supplemental Material).…”

Section: Resultsmentioning

confidence: 99%

“…In an effort to develop new CB 1 inverse agonist scaffolds, we analyzed the common pharmacophore of this class of compounds, which was proposed by Lange and Kruse (2005). This showed that the biaryl groups connecting to a central heteroaromatic ring are pivotal in forming aromatic stacking interactions with CB 1 receptors (McAllister et al, 2004;Shim et al, 2012). This brought our attention to the benzhydryl piperazine scaffold, which exhibits a similar structure to the common pharmacophore of CB 1 inverse agonists in lieu of the biaryl heteroaromatic ring moiety.…”

Section: Introductionmentioning

confidence: 99%

(4-(Bis(4-Fluorophenyl)Methyl)Piperazin-1-yl)(Cyclohexyl)Methanone Hydrochloride (LDK1229): A New Cannabinoid CB₁Receptor Inverse Agonist from the Class of Benzhydryl Piperazine Analogs

et al. 2014

Self Cite

View full text Add to dashboard Cite

Some inverse agonists of cannabinoid receptor type 1 (CB 1 ) have been demonstrated to be anorectic antiobesity drug candidates. However, the first generation of CB 1 inverse agonists, represented by rimonabant (SR141716A), otenabant, and taranabant, are centrally active, with a high level of psychiatric side effects. Hence, the discovery of CB 1 inverse agonists with a chemical scaffold distinct from these holds promise for developing peripherally active CB 1 inverse agonists with fewer side effects. We generated a new CB 1 inverse agonist, (4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)(cyclohexyl)methanone hydrochloride (LDK1229), from the class of benzhydryl piperazine analogs. This compound binds to CB 1 more selectively than cannabinoid receptor type 2, with a K i value of 220 nM. Comparable CB 1 binding was also observed by analogs 1-[bis (4-fluorophenyl)methyl]-4-cinnamylpiperazine dihydrochloride (LDK1203) and 1-[bis(4-fluorophenyl)methyl]-4-tosylpiperazine hydrochloride (LDK1222), which differed by the substitution on the piperazine ring where the piperazine of LDK1203 and LDK1222 are substituted by an alkyl group and a tosyl group, respectively. LDK1229 exhibits efficacy comparable with SR141716A in antagonizing the basal G protein coupling activity of CB 1 , as indicated by a reduction in guanosine 59-O-(3-thio)triphosphate binding. Consistent with inverse agonist behavior, increased cell surface localization of CB 1 upon treatment with LDK1229 was also observed. Although docking and mutational analysis showed that LDK1229 forms similar interactions with the receptor as SR141716A does, the benzhydryl piperazine scaffold is structurally distinct from the first-generation CB 1 inverse agonists. It offers new opportunities for developing novel CB 1 inverse agonists through the optimization of molecular properties, such as the polar surface area and hydrophilicity, to reduce the central activity observed with SR141716A.

show abstract

Probing the Interaction of SR141716A with the CB1 Receptor

Cited by 17 publications

References 50 publications

Beyond radio-displacement techniques for Identification of CB1 Ligands: The First Application of a Fluorescence-quenching Assay

Beyond radio-displacement techniques for Identification of CB1 Ligands: The First Application of a Fluorescence-quenching Assay

Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists

(4-(Bis(4-Fluorophenyl)Methyl)Piperazin-1-yl)(Cyclohexyl)Methanone Hydrochloride (LDK1229): A New Cannabinoid CB₁Receptor Inverse Agonist from the Class of Benzhydryl Piperazine Analogs

Contact Info

Product

Resources

About

Probing the Interaction of SR141716A with the CB1 Receptor

Cited by 17 publications

References 50 publications

Beyond radio-displacement techniques for Identification of CB1 Ligands: The First Application of a Fluorescence-quenching Assay

Beyond radio-displacement techniques for Identification of CB1 Ligands: The First Application of a Fluorescence-quenching Assay

Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists

(4-(Bis(4-Fluorophenyl)Methyl)Piperazin-1-yl)(Cyclohexyl)Methanone Hydrochloride (LDK1229): A New Cannabinoid CB1Receptor Inverse Agonist from the Class of Benzhydryl Piperazine Analogs

Contact Info

Product

Resources

About

(4-(Bis(4-Fluorophenyl)Methyl)Piperazin-1-yl)(Cyclohexyl)Methanone Hydrochloride (LDK1229): A New Cannabinoid CB₁Receptor Inverse Agonist from the Class of Benzhydryl Piperazine Analogs