Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor "hybrid" ligands.
Anandamide and the metabolically stabler analogs, (R)-1'-methyl-2'-hydroxy-ethyl-arachidonamide (Met-AEA) and N-(3-methoxy-4-hydroxy-benzyl)-arachidonamide (arvanil), are CB(1) cannabinoid and VR(1) vanilloid receptors agonists. We synthesized 1',1'-dimethylheptyl-arvanil (O-1839) and six other AEA analogs obtained by addition of either a hydroxy, cyano, or bromo group on the C-20 atom of 1,1'-dimethylpentyl-Met-AEA (O-1811, O-1812 and O-1860, respectively) or 1,1'-dimethylpentyl-arvanil (O-1856, O-1895 and O-1861, respectively). The compounds were tested for their (i) affinity for CB(1) and CB(2) receptors, (ii) capability to activate VR1 receptors, (iii) inhibitory effect on the anandamide hydrolysis and on the anandamide membrane transporter, and (iv) cannabimimetic activity in the mouse 'tetrad' of in vivo assays. O-1812 is the first ligand ever proven to be highly (500- to 1000-fold) selective for CB(1) vs both VR(1) and CB(2) receptors, while O-1861 is the first true "hybrid" agonist of CB(1)/VR(1) receptors and a compound with potential therapeutic importance. The activities of the seven compounds in vivo did not correlate with their activities at either CB(1) or VR(1) receptors, thus suggesting the existence of other brain sites of action mediating some of their neurobehavioral actions in mice.
Di Marzo
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Endocannabinoid Research Group, Istituto per la Chimica di Molecole di Interesse Biologico and Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, Via Toiano 6, 80072, Arco Felice (NA), Italy. vdimarzo@icmib.na.cnr.it
Bisogno
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De Petrocellis
L
L
Brandi
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I
Jefferson
R G
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Winckler
R L
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Davis
J B
JB
Dasse
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Mahadevan
A
A
Razdan
R K
RK
Martin
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D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D048588:Benzoxazines; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D003511:Cyclohexanols / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D006801:Humans; D008024:Ligands; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels; D014316:Tritium; D014407:Tumor Cells, Cultured
D001095:Arachidonic Acids; D048588:Benzoxazines; C469526:Cnr2 protein, rat; D003511:Cyclohexanols; D063388:Endocannabinoids; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C121153:arvanil; D014316:Tritium; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D002211:Capsaicin; D002118:Calcium; C078814:anandamide