Cannabinoids. Structure-activity studies related to 1,2-dimethylheptyl derivatives

Loev, Bernard; Bender, Paul E.; Dowalo, F.; Macko, Edward; Fowler, Philip J.

doi:10.1021/jm00269a002

Cited by 57 publications

(25 citation statements)

References 7 publications

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“…It has been proposed that there exists a hydrophobic binding pocket that interacts with the C3 alkyl chain of classical and nonclassical cannabinoids (12)(13)(14)(15)(16), a key pharmacophoric element for the CB1 receptor (17,18). In this regard, the identification of Cys-355 6.47 , located next to Trp-356 6.48 of the highly conserved CWXP motif, as a binding contact for the C3 alkyl chain of a nonclassical cannabinoid (19) is highly informative.…”

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confidence: 99%

Identification of Essential Cannabinoid-binding Domains

Shim

Bertalovitz

Kendall

2011

Journal of Biological Chemistry

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The classical cannabinoid agonist HU210, a structural analog of (؊)-⌬ 9 -tetrahydrocannabinol, binds to brain cannabinoid (CB1) receptors and activates signal transduction pathways. To date, an exact molecular description of the CB1 receptor is not yet available. Utilizing the minor binding pocket of the CB1 receptor as the primary ligand interaction site, we explored HU210 binding using lipid bilayer molecular dynamics (MD) simulations. Among the potential ligand contact residues, we identified residues Phe-174 (1-naphthalenyl)methanone (WIN55212-2)), and endocannabinoids (e.g. N-arachidonoylethanolamine and 2-arachidonoylglycerol), bind to the CB1 receptor and activate signal transduction pathways (3) in an agonist-specific manner (4). According to the two-state model of GPCR activation (5), these agonists stabilize the receptor in its active state, whereas an inverse agonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) (6, 7) stabilizes the receptor in its inactive state.The CB1 receptor is a valuable therapeutic target for a number of disorders, including the treatment of anorexia in patients who suffer from AIDS wasting syndrome, reducing nausea and vomiting associated with chemotherapy treatment (8), reducing spasticity in multiple sclerosis patients (9), the treatment of neurodegenerative disease (10), and relief of neuropathic pain in multiple sclerosis (11). The accumulated mutational and structure-activity relationship data for the CB1 receptor enable us to better understand the receptor-ligand interactions, as an exact molecular description of the CB1 receptor is not yet available.It has been proposed that there exists a hydrophobic binding pocket that interacts with the C3 alkyl chain of classical and nonclassical cannabinoids (12-16), a key pharmacophoric element for the CB1 receptor (17,18). In this regard, the identification of , located next to Trp-356 6.48 of the highly conserved CWXP motif, as a binding contact for the C3 alkyl chain of a nonclassical cannabinoid (19) is highly informative.3,4 The finding that Cys-285 6.47 of the ␤2 adrenergic receptor (␤2AR) became accessible to a thiol-reactive reagent only when the receptor was activated (20) suggests the corresponding residue of the CB1 receptor, Cys-355 6.47 , unavailable for ligand binding in the inactive state, becomes available in the active state as the Cys-355 6.47 moves into the binding core as a result of an anticlockwise rigid-body rotation of the transmembrane (TM) helix 6 (H6) (21). Thus, it appears that the hydrophobic pocket that interacts with the C3 alkyl chain of cannabinoids forms dynamically as the receptor shifts its equilibrium toward the active state. No residues, other than Cys- GPCR, G protein-coupled receptor; ⌬ 9 -THC, (Ϫ)-⌬ 9 -tetrahydrocannabinol; TM, transmembrane; H, TM helix; EC, extracellular loop; ␤2AR, ␤2 adrenergic receptor; MD, molecular dynamics; TME, Tris/Mg 2ϩ /EDTA; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; r.m.s.d., root-me...

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confidence: 99%

Identification of Essential Cannabinoid-binding Domains

Shim

Bertalovitz

Kendall

2011

Journal of Biological Chemistry

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“…However, more potent activity is needed for clinical use. It is known that modifications of the pentyl side chain of THC increase its potency [12]. In particular, extending the chain length to seven C-atoms and introducing branching close to the benzene ring leads to compounds with potencies that are 50 to 100 times greater than that of THC proper.…”

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On the Pharmacological Properties of Δ⁹‐Tetrahydrocannabinol (THC)

Costa

2007

Chemistry & Biodiversity

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Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant.

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“…However, a molecule more potent than THC-11 oic acid is needed for clinical use. It has been known for some time that certain modification of the pentyl side chain of THC increases its potency (8). Therefore, a derivative of THC-11 oic acid with a dimethylheptyl side chain was prepared and tested for analgesic and antiinflammatory activity in several animal models (9).…”

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confidence: 99%