New class of potent ligands for the human peripheral cannabinoid receptor

Gallant, Michel; Dufresne, Claude; Gareau, Yves; Guay, Daniel; Leblanc, Yves; Prasit, Petpiboon; Rochette, C.; Sawyer, Nicole; Slipetz, Deborah; Tremblay, Nathalie; Metters, Kathleen M.; Labelle, Marc

doi:10.1016/0960-894x(96)00426-x

Cited by 91 publications

(67 citation statements)

References 17 publications

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“…In our assay, GW405833 shows a 10-fold lower affinity for hCB 2 and behaved as an inverse agonist in our GTPgS assay. Our results are in accordance with those of Yao et al, who reported that GW405833 is a potent inverse agonist in both hCB 2 (16,29,30).…”

Section: Discussionsupporting

confidence: 93%

A PET Brain Reporter Gene System Based on Type 2 Cannabinoid Receptors

Vandeputte¹,

Evens²,

Toelen³

et al. 2011

J Nucl Med

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PET of gene expression in the brain may greatly facilitate neuroscience research and potential clinical implementation of gene or cell therapy of central nervous system diseases. To date, no adequate PET reporter system is available for the central nervous system because available tracers either do not cross the intact blood-brain barrier or have high background signals. Here we report the first, to our knowledge, PET reporter system for imaging gene expression in the intact brain. Methods: We selected the human type 2 cannabinoid receptor (hCB 2 ) as a reporter because of its low basal expression in the brain. An inactive mutant (D80N) was chosen so as not to interfere with signal transduction. As a reporter probe we used the 11 C-labeled CB 2 ligand, 11 C-GW405833, which readily crosses the blood-brain barrier. Dual-modality imaging lentiviral and adeno-associated viral vectors encoding both hCB 2 (D80N) and firefly luciferase or enhanced green fluorescent protein were engineered and validated in cell culture. Next, hCB 2 (D80N) was locoregionally overexpressed in rat striatum by stereotactic injection of lentiviral and adeno-associated viral vectors. Results: Kinetic PET revealed specific and reversible CB 2 binding of 11 C-GW405833 in the transduced rat striatum. hCB 2 and firefly luciferase expression was followed until 9 mo and showed similar kinetics. Both hCB 2 expression and enhanced green fluorescent protein expression were confirmed by immunohistochemistry. Conclusion: Dual-modality imaging viral vectors encoding hCB 2 (D80N) were engineered, and the reporter system was validated in different animal species. The results support the potential future clinical use of CB 2 as a PET reporter in the intact brain.

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Section: Discussionsupporting

confidence: 93%

A PET Brain Reporter Gene System Based on Type 2 Cannabinoid Receptors

Vandeputte¹,

Evens²,

Toelen³

et al. 2011

J Nucl Med

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“…The binding data for compounds that bind to CB 2 reported so far (24)(25)(26)(27)(28), as well as for HU-308 in the present paper, indicate that major differences exist between the structure-activity relationships (SAR) for binding to CB 1 and CB 2 . Although a free phenolic group in cannabinoid-type compounds is a basic structural feature for CB 1 binding and cannabimimetic activity (29), it is not required for CB 2 binding.…”

Section: Resultsmentioning

confidence: 90%

“…24). Most of these compounds exhibit only modest selectivity (25)(26)(27). Of particular relevance to the present work are cannabinoid-type compounds, such as L-758,656 and L-759,633, in which the phenolic group is blocked as a methyl ether.…”

Section: Resultsmentioning

confidence: 99%

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

Hanŭs

Breuer

Tchilibon

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

528

367

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Two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, present outside the CNS, in peripheral organs. There is evidence for the presence of CB2-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB2-specific agonist, code-named HU-308. This cannabinoid does not bind to CB1 (Ki > 10 M), but does so efficiently to CB2 (Ki ‫؍‬ 22.7 ؎ 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB2-transfected cells, but does so much less in CB1-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB1. However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB2 antagonist SR-144528, but not by the CB1 antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.

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“…25 Figure 6. Mock plates received 0.8% DMSO in assay buffer (no compounds), followed by addition of 25 µM veratridine.…”

Section: Resultsmentioning

confidence: 99%

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

Benjamin

Pruthi²,

Olanrewaju³

et al. 2006

SLAS Discovery

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Voltage-gated sodium channels (NaChs) are relevant targets for pain, epilepsy, and a variety of neurological and cardiac disorders. Traditionally, it has been difficult to develop structure-activity relationships for NaCh inhibitors due to rapid channel kinetics and state-dependent compound interactions. Membrane potential (V m ) dyes in conjunction with a high-throughput fluorescence imaging plate reader (FLIPR) offer a satisfactory 1st-tier solution. Thus, the authors have developed a FLIPR V m assay of rat Na v 1.2 NaCh. Channels were opened by addition of veratridine, and V m dye responses were measured. The IC 50 values from various structural classes of compounds were compared to the resting state binding constant (K r ) and inactivated state binding constant (K i ) obtained using patch-clamp electrophysiology (EP). The FLIPR values correlated with K i but not K r . FLIPR IC 50 values fell within 0.1-to 1.5-fold of EP K i values, indicating that the assay generally reports use-dependent inhibition rather than resting state block. The Library of Pharmacologically Active Compounds (LOPAC, Sigma) was screened. Confirmed hits arose from diverse classes such as dopamine receptor antagonists, serotonin transport inhibitors, and kinase inhibitors. These data suggest that NaCh inhibition is inherent in a diverse set of biologically active molecules and may warrant counterscreening NaChs to avoid unwanted secondary pharmacology. (Journal of Biomolecular Screening 2006: 29-39)

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New class of potent ligands for the human peripheral cannabinoid receptor

Cited by 91 publications

References 17 publications

A PET Brain Reporter Gene System Based on Type 2 Cannabinoid Receptors

A PET Brain Reporter Gene System Based on Type 2 Cannabinoid Receptors

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

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New class of potent ligands for the human peripheral cannabinoid receptor

Cited by 91 publications

References 17 publications

A PET Brain Reporter Gene System Based on Type 2 Cannabinoid Receptors

A PET Brain Reporter Gene System Based on Type 2 Cannabinoid Receptors

HU-308: A specific agonist for CB 2 , a peripheral cannabinoid receptor

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

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HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor