Cannabinol Derivatives:  Binding to Cannabinoid Receptors and Inhibition of Adenylylcyclase

Rhee, Man Hee; Vogel, Zvi; Barg, Jacob; Bayewitch, Michael; Levy, Rivka; Hanŭs, L; Breuer, Aviva; Mechoulam, Raphael

doi:10.1021/jm970126f

Cited by 161 publications

(118 citation statements)

References 28 publications

(91 reference statements)

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“…3C), indicating that like endocannabinoids (19), OS binds to and activates a Gi-protein coupled receptor (GPCR). Binding analyses for CB 1 and CB 2 cannabinoid receptors using synaptosomal membranes prepared from rat brains and transfected cells, respectively (20), showed that neither the D nor L form of synthetic OS binds to these receptors up to concentrations of 10 μM. Furthermore, OS stimulated the number of CB 2 -null osteoblasts in a manner similar to that observed in wild-type osteoblasts (Fig.…”

Section: Mitogenic Signaling Of Os In Osteoblasts Involvesmentioning

confidence: 67%

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Smoum

Bar²,

Tan

et al. 2010

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

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Bone mass is determined by a continuous remodeling process, whereby the mineralized matrix is being removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. Here we report the presence of endogenous amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) in mouse bone. Of these compounds, N-oleoyl-L-serine (OS) had the highest activity in an osteoblast proliferation assay. In these cells, OS triggers a Gi-protein-coupled receptor and Erk1/2. It also mitigates osteoclast number by promoting osteoclast apoptosis through the inhibition of Erk1/2 phosphorylation and receptor activator of nuclear-κB ligand (RANKL) expression in bone marrow stromal cells and osteoblasts. In intact mice, OS moderately increases bone volume density mainly by inhibiting bone resorption. However, in a mouse ovariectomy (OVX) model for osteoporosis, OS effectively rescues bone loss by increasing bone formation and markedly restraining bone resorption. The differential effect of exogenous OS in the OVX vs. intact animals is apparently a result of an OVX-induced decrease in skeletal OS levels. These data show that OS is a previously unexplored lipid regulator of bone remodeling. It represents a lead to antiosteoporotic drug discovery, advantageous to currently available therapies, which are essentially either proformative or antiresorptive.fatty acyl amides I n mammals, including humans, bone mass is determined by an unremitting remodeling process whereby the mineralized matrix is continuously removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. This process is regulated by autocrine/paracrine factors, such as receptor activator of nuclear-κB ligand (RANKL), osteoprotegerin (OPG), bone morphogenetic proteins, and Wnt, as well as circulating hormones (e.g., sex steroids, parathyroid hormone) and brain-derived signals (e.g., sympathetic, pituitary) (1-3). Imbalanced bone remodeling leads to skeletal pathologies, mainly osteoporosis, the most common degenerative disorder in affluent societies, which results from a net increase in bone resorption (4). Identification of endogenous constituents, which regulate bone remodeling and skeletal mass, contributes to the elucidation of the mechanisms involved in this process and offers promise for developing novel antiosteoporotic pharmacotherapy.Amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) represent a major group of endogenous lipids. In mammalian tissues they have numerous physiological functions. For example, anandamide (arachidonoyl ethanolamide) is the first identified endogenous psychoactive ligand of cannabinoid receptors (5); arachidonoyl serine is an endogenous vasodilator, which does not bind to the cannabinoid receptors (6); and oleoyl ethanolamide is an endogenous structural analog to anandamide that regulates food intake through the activation of GPR 119 (7, 8). The well-established biosynthetic tendency to follow existing p...

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Section: Mitogenic Signaling Of Os In Osteoblasts Involvesmentioning

confidence: 67%

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Smoum

Bar²,

Tan

et al. 2010

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

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“…⌬ 9 -THC Effects in CB1 ؊/؊ Mice. We next analyzed the effects of ⌬ 9 -THC, the major psychoactive compound in C. sativa preparations (6), in CB1 receptor knockout mice, which is at least 100 times less potent than HU210 at the CB1 receptor (9,28,29). Administration of ⌬…”

Section: Resultsmentioning

confidence: 99%

Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice

Zimmer

Hohmann

et al. 1999

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

956

693

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ABSTRACT⌬ 9 -Tetrahydrocannabinol (⌬ 9 -THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. ⌬ 9 -THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found ⌬ 9 -THC-induced analgesia in the tail-f lick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after ⌬ 9 -THC administration. Thus, most, but not all, CNS effects of ⌬ 9 -THC are mediated by the CB1 receptor.

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“…The replacement of the pentyl group with a dimethylheptyl group at position 3 of the cyclic and bicyclic cannabinoids was found to increase ligand affinity to CB 1 and CB 2 . It was therefore inferred that a hydrophobic region in both receptors accommodates this hydrophobic side chain (Rhee et al, 1997;Howlett, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…This assay was performed as described previously Rhee et al, 1997). Frozen pellets of transfected cells were homogenized in 2 ml of binding buffer per plate, and 100-l aliquots of crude cell homogenates containing 15-20 g protein [as determined by the method of Bradford (1976)] were mixed with 300 fmol of the high-affinity cannabinoid agonist [ 3 H]HU-243 in 1.5-ml Eppendorf tubes in a final volume of 1 ml of 50 mM Tris-HCl, 5 mM MgCl 2 , 10 mM CaCl 2 , 2.5 mM EDTA (pH 7.4), and 2 mg/ml fatty acid-free bovine serum albumin.…”

Section: Binding Of [ 3 H]hu-243mentioning

confidence: 99%

Functional Role of Tryptophan Residues in the Fourth Transmembrane Domainof the CB₂ Cannabinoid Receptor

Rhee

Nevo

Bayewitch

et al. 2000

Journal of Neurochemistry

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Several tryptophan (Trp) residues are conserved in G protein-coupled receptors (GPCRs). Relatively little is known about the contribution of these residues and especially of those in the fourth transmembrane domain in the function of the CB 2 cannabinoid receptor. Replacing W158 (very highly conserved in GPCRs) and W172 (conserved in CB 1 and CB 2 cannabinoid receptors but not in many other GPCRs) of the human CB 2 receptor with A or L or with F or Y produced different results. We found that the conservative change of W172 to F or Y retained cannabinoid binding and downstream signaling (inhibition of adenylyl cyclase), whereas removal of the aromatic side chain by mutating W172 to A or L eliminated agonist binding. W158 was even more sensitive to being mutated. We found that the conservative W158F mutation retained wild-type binding and signaling activities. However, W158Y and W158A mutants completely lost ligand binding capacity. Thus, the Trp side chains at positions 158 and 172 seem to have a critical, but different, role in cannabinoid binding to the human CB 2 receptor.

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Cannabinol Derivatives: Binding to Cannabinoid Receptors and Inhibition of Adenylylcyclase

Cited by 161 publications

References 28 publications

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice

Functional Role of Tryptophan Residues in the Fourth Transmembrane Domainof the CB₂ Cannabinoid Receptor

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Cannabinol Derivatives: Binding to Cannabinoid Receptors and Inhibition of Adenylylcyclase

Cited by 161 publications

References 28 publications

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice

Functional Role of Tryptophan Residues in the Fourth Transmembrane Domainof the CB2 Cannabinoid Receptor

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Functional Role of Tryptophan Residues in the Fourth Transmembrane Domainof the CB₂ Cannabinoid Receptor