New Analogs of Tetrahydrocannabinol. XIX

Adams, Roger; Harfenist, M.; Loewe, S.

doi:10.1021/ja01173a023

Cited by 76 publications

(33 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several active principles have been extracted from the plant (Woltner et al, 1942; Lerner, 1963;Ropp, 1960;Davis et al, 1963;Gaoni and Mcchoulan, 1964;Mechoulan and Shvo, 1963;Valle and llypolito, 1964) of which tetrahydrocannabinol is considered very potent as measured by the dog locomotor ataxia and the rabbit corneal areflexia methods (Loeive, 1950). Synthesis of analogs of tetrahydrocannabinol, some of which with potencies considerably greater than that of the natural compound, had been reported (Adams and Raker, 1940;Adams et al, 1949). Tentatives to find therapeutic applications for marihuana or its principles had been hindered by the unpredictability of their effects on man.…”

Section: By J Sa L U S T Ia N O K H O S H In O ** and E A Carlinimentioning

confidence: 99%

Effects of Cannabis Sativa and Chlorpromazine on Mice as Measured by Two Methods Used for Evaluation of Tranquilizing Agents

Salustiano¹,

Hoshino²,

Carlini³

1966

Pharmacology

View full text Add to dashboard Cite

Section: By J Sa L U S T Ia N O K H O S H In O ** and E A Carlinimentioning

confidence: 99%

Effects of Cannabis Sativa and Chlorpromazine on Mice as Measured by Two Methods Used for Evaluation of Tranquilizing Agents

Salustiano¹,

Hoshino²,

Carlini³

1966

Pharmacology

View full text Add to dashboard Cite

“…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.…”

mentioning

confidence: 99%

Identification of Essential Cannabinoid-binding Domains

Shim

Bertalovitz

Kendall

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

“…In a very early SAR finding, the importance of the side chain was first demonstrated by Adams (Adams, 1942;Adams et al, 1949) where the 1V,1V-dimethylheptyl analogue was shown to be 100-fold more potent than the n-hexyl analogue in the D 6a,10a -THC series. Subsequent SAR studies on classical cannabinoids (CCs) have recognized the C-3 alkyl side chain as the most critical pharmacophoric group (Howlett et al, 2002;Khanolkar et al, 2000;Makriyannis and Rapaka, 1990;Palmer et al, 2000Palmer et al, , 2002Thakur et al, 2005a).…”

Section: Side Chain Sar Of Cannabinoids and Endocannabinoidsmentioning

confidence: 99%