A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid
- Vincenzo Di Marzo1,
- Graeme Griffin3,
- Luciano De Petrocellis2,
- Ines Brandi1,
- Tiziana Bisogno1,
- William Williams4,
- Mark C. Grier4,
- Sanjitha Kulasegram4,
- Anu Mahadevan4,
- Raj K. Razdan4 and
- Billy R. Martin3
- 1Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Pozzuoli (Napoli), Italy (V.D.M., I.B., T.B.); and 2Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, Comprensorio Olivetti, Pozzuoli (Napoli), Italy (L.D.P.); 3Department of Pharmacology and Toxicology, Medical School of Virginia, Virginia Commonwealth University, Richmond, Virginia (G.G., B.R.M.); and 4Organix Inc., Woburn, Massachusetts (W.W., M.C.G., S.K., A.M., R.K.R.)
- Dr. Vincenzo Di Marzo, Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Fabbricato 70, 80078 Pozzuoli (Napoli), Italy. E-mail:vdimarzo{at}icmib.na.cnr.it
Abstract
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 VR1and AMT but exhibited little affinity for CB1 receptors. The urea analog was a potent FAAH inhibitor (IC50 = 2.0 μM). 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 ∼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.
Footnotes
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Supported by Grant 3933 (to V.D.M.) from Ministero dell'Universitá e della Ricerca Scientifica e Technologica and National Institute on Drug Abuse (DA-03672 and DA-08904 and DA-09789 to R.K.R.).
- Abbreviations:
- VR1
- vanilloid receptor type 1
- hVR1
- human VR1
- CB1
- cannabinoid receptor type 1
- AMT
- anandamide membrane transporter
- FAAH
- fatty acid amide hydrolase
- AEA
- arachidonoylethanolamide (anandamide)
- BSA
- bovine serum albumin
- [35S]GTPγS
- guanosine 5′-O -(3- [35 S]thiotriphosphate)
- HEK
- human embryonic kidney
- %MPE
- percent maximal possible effect
- CP55940
- (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclo-hesanol
- SR141716A
- N-piperidino-5-(4-chlorophenyl)1-(2,4-dichloro-phenyl)-4-methylpyrazole-3-carboxamide
- AM404
- N-(4-hydroxyphenyl)-arachidonamide
- VDM13
- N-(5-methoxy-tryptomin)-arachidonamide
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- Received August 30, 2001.
- Accepted November 15, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
