A structure/activity relationship study on arvanil, an endocannabinoid and vanilloid hybrid.
Arvanil, a structural "hybrid" between the endogenous cannabinoid CB1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR1 (vanilloid receptor type 1), inhibits the anandamide membrane transporter (AMT), and induces cannabimimetic responses in mice. Novel arvanil derivatives prepared by N-methylation, replacement of the amide with urea and thiourea moieties, and manipulation of the vanillyl group were evaluated for their ability to bind/activate CB1 receptors, activate VR1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compounds did not stimulate the CB1 receptor. Methylation of the amide group decreased the activity at VR1, AMT, and FAAH. On the aromatic ring, the substitution of the 3-methoxy group with a chlorine atom or the lack of the 4-hydroxy group decreased the activity on VR1 and AMT, but not the affinity for CB1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR1 and AMT but exhibited little affinity for CB1 receptors. The urea analog was a potent FAAH inhibitor (IC50 = 2.0 microM). A water-soluble analog of arvanil, O-2142, was as active on VR1, much less active on AMT and CB1, and more potent on FAAH. All compounds induced a response in the mouse "tetrad", particularly those with EC50 <10 nM on VR1. However, the most potent compound, N-N'-di-(3-chloro-4-hydroxy)benzyl-arachidonamide (O-2093, ED50 approximately 0.04 mg/kg), did not activate VR1 or CB1 receptors. Our findings suggest that VR1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.
Di Marzo
Vincenzo
V
Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Pozzuoli, Napoli, Italy. vdimarzo@icmib.na.cnr.it
Griffin
Graeme
G
De Petrocellis
Luciano
L
Brandi
Ines
I
Bisogno
Tiziana
T
Williams
William
W
Grier
Mark C
MC
Kulasegram
Sanjitha
S
Mahadevan
Anu
A
Razdan
Raj K
RK
Martin
Billy R
BR
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry; D001522:Behavior, Animal / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000737:chemistry / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D063388:Endocannabinoids; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D053284:Polyunsaturated Alkamides; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000737:chemistry; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D002211:Capsaicin; D002352:Carrier Proteins; D063388:Endocannabinoids; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C121153:arvanil; C078814:anandamide