AM630 is an inverse agonist at the human cannabinoid CB1 receptor

Landsman, Robert S.; Makriyannis, Alexandros; Deng, Hongfeng; Consroe, Paul; Roeske, William R.; Yamamura, Henry I.

doi:10.1016/s0024-3205(97)01187-9

Cited by 48 publications

(36 citation statements)

References 7 publications

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“…Other mice received WIN 55,212-2, (10 g /day) together with the peptides. Mice receiving only A [25][26][27][28][29][30][31][32][33][34][35] showed significantly reduced levels of the neuronal proteins calbindin and -tubulin, matching similar findings in human Alzheimer's brains. These mice also showed a marked inability to improve on a Morris water maze test compared with controls.…”

Section: In Vivo Studiessupporting

confidence: 59%

“…Molina-Holgardo et al [43] reported that AMPA-induced neuronal toxicity in vitro was blocked by 1 M of the CB2 antagonist AM630. However, this concentration is likely to have saturated both CB1 and CB2 receptors [34].…”

Section: The Potential For Cb2-mediated Psychoactive Effectsmentioning

confidence: 99%

“…Mice were subject to intracerebroventricular daily injections of A [25][26][27][28][29][30][31][32][33][34][35] or a control peptide for 7 days. Other mice received WIN 55,212-2, (10 g /day) together with the peptides.…”

Section: In Vivo Studiesmentioning

confidence: 99%

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The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

Ashton

Glass²

2007

278

249

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Endocannabinoids are released following brain injury and may protect against excitotoxic damage during the acute stage of injury. Brain injury also activates microglia in a secondary inflammatory phase of more widespread damage. Most drugs targeting the acute stage are not effective if administered more than 6 hours after injury. Therefore, drugs targeting microglia later in the neurodegenerative cascade are desirable. We have found that cannabinoid CB2 receptors are upregulated during the activation of microglia following brain injury. Specifically, CB2-positive cells appear in the rat brain following both hypoxia-ischemia (HI) and middle cerebral artery occlusion (MCAO). This may regulate post-injury microglial activation and inflammatory functions. In this paper we review in vivo and in vitro studies of CB2 receptors in microglia, including our results on CB2 expression post-injury. Taken together, studies show that CB2 is upregulated during a process in which microglia become primed to proliferate, and then become fully reactive. In addition, CB2 activation appears to prevent or decrease microglial activation. In a rodent model of Alzheimer's disease microglial activation was completely prevented by administration of a selective CB2 agonist. The presence of CB2 receptors in microglia in the human Alzheimer's diseased brain suggests that CB2 may provide a novel target for a range of neuropathologies. We conclude that the administration of CB2 agonists and antagonists may differentially alter microglia-dependent neuroinflammation. CB2 specific compounds have considerable therapeutic appeal over CB1 compounds, as the exclusive expression of CB2 on immune cells within the brain provides a highly specialised target, without the psychoactivity that plagues CB1 directed therapies.

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Section: In Vivo Studiessupporting

confidence: 59%

Section: The Potential For Cb2-mediated Psychoactive Effectsmentioning

confidence: 99%

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The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

Ashton

Glass²

2007

278

249

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“…The aminoalkylindole AM630 was first reported as a cannabinoid receptor antagonist (Pertwee et al, 1995). Later, this compound was identified as a CB 1 R and CB 2 R inverse agonist (Landsman et al, 1998;Ross et al, 1999). Interestingly, Bolognini et al, (2012) showed that AM630 may act as a protean agonist.…”

Section: H]-cp55940 and [mentioning

confidence: 99%

Two Affinity Sites of the Cannabinoid Subtype 2 Receptor Identified by a Novel Homogeneous Binding Assay

Martínez‐Pinilla

Rabal

Reyes‐Resina

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Endocannabinoids act on G protein-coupled receptors that are considered potential targets for a variety of diseases. There are two different cannabinoid receptor types: ligands for cannabinoid type 2 receptors (CB 2 Rs) show more promise than those for cannabinoid type 1 receptors (CB 1 Rs) because they lack psychotropic actions. However, the complex pharmacology of these receptors, coupled with the lipophilic nature of ligands, is delaying the translational success of medications targeting the endocannabinoid system. We here report the discovery and synthesis of a fluorophore-conjugated CB 2 R-selective compound, CM-157propan-1-amine), which was useful for pharmacological characterization of CB 2 R by using a timeresolved fluorescence resonance energy transfer assay. This methodology does not require radiolabeled compounds and may be undertaken in homogeneous conditions and in living cells (i.e., without the need to isolate receptor-containing membranes).The affinity of the labeled compound was similar to that of the unlabeled molecule. Time-resolved fluorescence resonance energy transfer assays disclosed a previously unreported second affinity site and showed conformational changes in CB 2 R forming receptor heteromers with G protein-coupled receptor GPR55, a receptor for l-a-lysophosphatidylinositol. The populations displaying subnanomolar and nanomolar affinities were undisclosed in competitive assays using a well known cannabinoid receptor ligand, AM630 (1-[2-(morpholin-4-yl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-6-iodoindole), and TH-chrysenediol, not previously tested on binding to cannabinoid receptors. Variations in binding parameters upon formation of dimers with GPR55 may reflect decreases in binding sites or alterations of the quaternary structure of the macromolecular G protein-coupled receptor complexes. In summary, the homogeneous binding assay described here may serve to better characterize agonist binding to CB 2 R and to identify specific properties of CB 2 R on living cells.

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“…However, the role of CB 2 receptor-expressing microglia in neuropathic pain, specifically in SCI pain, remains to be determined. Alternatively, it is possible that some selective CB 2 receptor antagonists have inverse agonist as well as antagonist properties, such that the observed "antagonism" is really an increase in pain caused by the "antagonist" (Landsman et al, 1998;Portier et al, 1999;Ross et al, 1998). Finally, it may be the case that CB 2 receptor activity is found in some but not all neuropathic pain models.…”

Section: Effect Of Cannabinoid Antagonists On the Antinociceptive Effmentioning

confidence: 99%

Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury

Hama

Sagen

2007

Experimental Neurology

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Spinal cord injury (SCI) pain exhibits many symptoms associated with peripheral neuropathic pain, including increased tactile hypersensitivity. One novel approach to ameliorate SCI pain is the use of cannabinoid (CB) ligands. The current study evaluated the efficacy of the nonselective CB receptor agonist WIN 55,212-2 on tactile hypersensitivity in rats following a brief compression to the thoracic spinal cord. The withdrawal thresholds of the hind paws following SCI were significantly decreased, indicating tactile hypersensitivity. Systemic injection of WIN 55,212-2 increased withdrawal thresholds in a dose-dependent manner. Pretreatment with the CB 1 receptor subtype-selective antagonist AM 251 completely abolished the antinociceptive effect of WIN 55,212-2 whereas pretreatment with the CB 2 receptor subtype-selective antagonist AM 630 did not alter the antinociceptive effect of WIN 55,212-2. These data indicate that a CB 1 selective agonist may be novel therapeutic treatment for clinical SCI pain. KeywordsAM 251; AM 630; allodynia; chronic pain; CB 1 receptor; neuropathic pain Trauma or disease to either the peripheral or central nervous system leads to persistent pain. There are few effective treatments for patients with chronic neuropathic pain. The cannabinoids show promise in alleviating peripheral neuropathic pain, which in turn, may have efficacy on central neuropathic pain states.Studies in rats indicate that the cannabinoid receptors (subtypes CB 1 and CB 2 ) have key roles in modulating pain, especially neuropathic pain. The CB 1 receptor has been identified in the rat dorsal root ganglia, spinal cord, and brain areas relevant to the processing of pain-related information (Farquhar-Smith et al., 2000;Hohmann et al., 1999;Tsou et al., 1998). There are numerous studies in rat models of peripheral neuropathic pain that demonstrate significant suppression of thermal and mechanical hypersensitivity with a non-selective CB receptor agonist, which is attenuated with a selective CB 1 receptor antagonist (Bridges et al., 2001;Fox et al., 2001;Herzberg et al., 1997;Pascual et al., 2005;Ulugol et al., 2004). However, a role for the CB 1 receptor in rats with central neuropathic pain caused by a spinal cord injury (SCI) has not been examined. The current study evaluated the effect of the non-selective CB receptor agonist WIN 55,212-2 in a rat model of neuropathic pain induced by compression of the spinal Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Gatley et al., 1996;Pertwee et al., 1995). NIH Public AccessSurgical and behavioral testing procedures were revi...

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AM630 is an inverse agonist at the human cannabinoid CB1 receptor

Cited by 48 publications

References 7 publications

The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

Two Affinity Sites of the Cannabinoid Subtype 2 Receptor Identified by a Novel Homogeneous Binding Assay

Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury

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