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.