DEXANABINOL


Synonyms	11-oh-thc Dexanabinol HU-210 HU-211 PA-50211 PRS-211007 PRS-211007-000 Sinnabidol
Status
Molecule Category	UNKNOWN
UNII	R6VT8U5372
EPA CompTox	DTXSID40150235


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	SSQJFGMEZBFMNV-PMACEKPBSA-N
Smiles	CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@H]1CC=C(CO)C[C@H]21
InChI	InChI=1S/C25H38O3/c1-6-7-8-9-12-24(2,3)18-14-21(27)23-19-13-17(16-26)10-11-20(19)25(4,5)28-22(23)15-18/h10,14-15,19-20,26-27H,6-9,11-13,16H2,1-5H3/t19-,20-/m0/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C25H38O3
Molecular Weight	386.58
AlogP	6.22
Hydrogen Bond Acceptor	3.0
Hydrogen Bond Donor	2.0
Number of Rotational Bond	7.0
Polar Surface Area	49.69
Molecular species	NEUTRAL
Aromatic Rings	1.0
Heavy Atoms	28.0

Reference

Journal : J. Med. Chem.

Title : Derivation of a pharmacophore model for anandamide using constrained conformational searching and comparative molecular field analysis.

PubMed ID : 9784095

DOI : 10.1021/jm970239z

Year : 1998

Volume : 41

Issue : 22

First Page : 4207

Last Page : 4215

Authors : Tong W, Collantes ER, Welsh WJ, Berglund BA, Howlett AC.

Abstract : Constrained molecular dynamics simulations on anandamide, together with a systematic distance comparison search, have revealed a specific low-energy conformer whose spatial disposition of the pharmacophoric elements closely matches that of HHC. This conformer enables near superposition of the following: (1) the oxygen of the carboxyamide and the phenolic hydroxyl group of HHC, (2) the hydroxyl group of the ethanol and the cyclohexyl hydroxyl group of HHC, (3) the alkyl tail and the lipophilic side chain of HHC, and (4) the polyolefin loop and the tricyclic ring structure of HHC. The close matching of common pharmacophoric elements of anandamide with HHC offers persuasive evidence of the biological relevance of this conformer. The proposed pharmacophore model was capable of discriminating between structurally related compounds exhibiting different pharmacological potency for the CB1 cannabinoid receptor, i.e., anandamide and N-(2-hydroxyethyl)prostaglandinamide. Furthermore, a 3D-QSAR model was derived using CoMFA for a training set of 29 classical and nonclassical analogues which rationalized the binding affinity in terms of steric and electrostatic properties and, more importantly, which predicted the potency of anandamide in excellent agreement with experimental data. The ABC tricyclic HU-210/HU-211 and ACD tricyclic CP55,243/CP55,244 enantiomeric pairs were employed as test compounds to validate the present CoMFA model. For each enantiomeric pair, the CoMFA-predicted log Ki values correctly identified that enantiomer exhibiting the higher affinity for the receptor.

Reference

Journal : J. Med. Chem.

Title : Substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one as CB1 cannabinoid receptor ligands: synthesis and pharmacological evaluation.

PubMed ID : 15801840

DOI : 10.1021/jm049263k

Year : 2005

Volume : 48

Issue : 7

First Page : 2509

Last Page : 2517

Authors : Muccioli GG, Martin D, Scriba GK, Poppitz W, Poupaert JH, Wouters J, Lambert DM.

Abstract : A set of 30 substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one (thiohydantoins) derivatives was synthesized, and their affinity for the human CB(1) cannabinoid receptor has been evaluated. These compounds are derived from the previously described cannabinoid ligands 5,5'-diphenylimidazolidine-2,4-dione (hydantoins). The replacement of the oxygen by a sulfur leads to an increase of the affinity while the function-i.e., inverse agonism-determined by [(35)S]GTPgammaS experiments remains unaffected. Finally, to evaluate the molecular parameters that could influence the affinity of the thiohydantoins, molecular electrostatic potential as well as lipophilicity calculations were undertaken on representative thiohydantoins and hydantoins derivatives. In conclusion, 5,5'-bis-(4-iodophenyl)-3-butyl-2-thioxoimidazolidin-4-one (31) and 3-allyl-5,5'-bis(4-bromophenyl)-2-thioxoimidazolidin-4-one (32) possess the highest affinity for the CB(1) cannabinoid receptor described to date for the hydantoin and thiohydantoins series when compared in a same bioassay.

Reference

Journal : J. Med. Chem.

Title : Virtual screening of novel CB2 ligands using a comparative model of the human cannabinoid CB2 receptor.

PubMed ID : 16279774

DOI : 10.1021/jm050565b

Year : 2005

Volume : 48

Issue : 23

First Page : 7166

Last Page : 7171

Authors : Salo OM, Raitio KH, Savinainen JR, Nevalainen T, Lahtela-Kakkonen M, Laitinen JT, Järvinen T, Poso A.

Abstract : To identify novel selective CB2 lead compounds, a comparative model of the CB2 receptor was constructed using the high-resolution bovine rhodopsin X-ray structure as a template. The CB2 model was utilized both in building the database queries and in filtering the hit compounds by a docking and scoring method. In G-protein activation assays, 1-isoquinolyl[3-(trifluoromethyl)phenyl]methanone (40, NRB 04079) was found to act as a selective agonist at the human CB2 receptor.

Reference

Journal : J. Med. Chem.

Title : Design, synthesis, and binding studies of new potent ligands of cannabinoid receptors.

PubMed ID : 16279794

DOI : 10.1021/jm0501533

Year : 2005

Volume : 48

Issue : 23

First Page : 7343

Last Page : 7350

Authors : Brizzi A, Brizzi V, Cascio MG, Bisogno T, Sirianni R, Di Marzo V.

Abstract : Despite their different chemical structures, delta9-tetrahydrocannabinol (THC) and anandamide (AEA) have common pharmacological properties. This study was aimed at finding new cannabinoid receptor ligands that overcome the instability of AEA and its analogues. To this end we planned the synthesis of a series of compounds which retained both a rigid structure, like that of plant cannabinoids, and a flexible portion similar to that of anandamide. Binding studies on CB1 and CB2 receptors, anandamide membrane transporter (AMT), and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds have high affinity and specificity for cannabinoid CB1 and CB2 receptors. Compound 25 is a potent CB1 and CB2 ligand, with affinity constants significantly lower than AEA and similar to WIN 55-212, compound 52 is a potent CB2 ligand, although not very selective over CB1 receptors, and compound 43 is CB2 ligand, with at least a 26-fold selectivity over CB1 receptors. Compound 25 behaved as a inverse agonist at CB1 receptors as assessed in the cyclic AMP functional assay.

Reference

Journal : J. Med. Chem.

Title : 1-Benzhydryl-3-phenylurea and 1-benzhydryl-3-phenylthiourea derivatives: new templates among the CB1 cannabinoid receptor inverse agonists.

PubMed ID : 16279809

DOI : 10.1021/jm0503906

Year : 2005

Volume : 48

Issue : 23

First Page : 7486

Last Page : 7490

Authors : Muccioli GG, Wouters J, Scriba GK, Poppitz W, Poupaert JH, Lambert DM.

Abstract : New 1-benzhydryl-3-phenylurea derivatives and their 1-benzhydryl-3-phenylthiourea isosteres were synthesized and evaluated for their human CB1 and CB2 cannabinoid receptor affinity. These compounds proved to be selective CB1 cannabinoid receptor ligands, acting as inverse agonists in a [35S]-GTPgammaS assay. The affinity of 3,5,5'-triphenylimidazolidine-2,4-dione and 3,5,5'-triphenyl-2-thioxoimidazolidin-4-one derivatives, possessing the 1-benzhydryl-3-phenylurea and 1-benzhydryl-3-phenylthiourea moiety, respectively, was also evaluated. In conclusion, the 1-benzhydryl-3-phenylurea scaffold seems to be a new interesting template of CB1 cannabinoid receptor inverse agonists.

Reference

Journal : J. Med. Chem.

Title : 1-Benzhydryl-3-phenylurea and 1-benzhydryl-3-phenylthiourea derivatives: new templates among the CB1 cannabinoid receptor inverse agonists.

PubMed ID : 16279809

DOI : 10.1021/jm0503906

Year : 2005

Volume : 48

Issue : 23

First Page : 7486

Last Page : 7490

Authors : Muccioli GG, Wouters J, Scriba GK, Poppitz W, Poupaert JH, Lambert DM.

Reference

Journal : Bioorg. Med. Chem.

Title : Design, synthesis, binding, and molecular modeling studies of new potent ligands of cannabinoid receptors.

PubMed ID : 17561406

DOI : 10.1016/j.bmc.2007.05.060

Year : 2007

Volume : 15

Issue : 16

First Page : 5406

Last Page : 5416

Authors : Brizzi A, Cascio MG, Brizzi V, Bisogno T, Dinatolo MT, Martinelli A, Tuccinardi T, Di Marzo V.

Abstract : In our ongoing program aimed at the design, synthesis, and biological evaluation of novel cannabinoid receptor ligands derived from olivetol and hexyl-resorcinol, we have designed a structural model for new derivatives on the basis of a previous study. Here we report the synthesis, binding, and molecular modeling studies of new potent compounds with high affinity toward CB(1) and CB(2) receptors. Compounds with amidic 'heads' with alkyloxy chains varying in length from 8 to 12 carbon atoms showed nanomolar affinity for both receptors, depending on the type of aromatic backbone. Two of the new compounds, although not very potent, exhibit selectivity for CB(1) receptors (CB(1)/CB(2)=0.07 and 0.08, respectively). Molecular modeling studies fitted this new class of cannabinoid ligands into a CB(1) receptor model, and the qualitative analysis of the results was in general agreement with the CB(1) affinity constants observed experimentally for these derivatives.

Assay Description	Organism	Bioactivity
Displacement of [3H]CP-55940 binding to Cannabinoid receptor 1 in rat brain membranes	None	360.0 nM
Inhibition of [3H]SR-141,716A binding to human CB1 receptor expressed in CHO cells	Homo sapiens	18.6 nM
Agonist activity at human CB2 receptor transfected in CHO cells by [35]GTPgamma binding assay	Homo sapiens	0.2512 nM
Displacement of [3H]CP-55940 from human CB2 receptor expressed in COS cells	Homo sapiens	150.0 nM
Displacement of [3H]SR141716A from human CB1 receptor expressed in CHO cells	Homo sapiens	19.0 nM
Activity at human CB1 receptor by [35S]GTP-gamma-S binding stimulation assay	Homo sapiens	0.6 nM
Displacement of [3H]CP-55940 from human CB2 receptor expressed in HEK cells	Homo sapiens	0.15 nM

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Cross References

Resources	Reference
ChEMBL	CHEMBL334533
DrugBank	DB06444
FDA SRS	R6VT8U5372
PubChem	107778
SureChEMBL	SCHEMBL1649687
ZINC	ZINC000003799010

CONTENTS

Structure
Chemical and Physical Properties
Related Entries