Arvanil, a structural "hybrid" between the endogenous cannabinoid CB 1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR 1 (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 CB 1 receptors, activate VR 1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compounds did not stimulate the CB 1 receptor. Methylation of the amide group decreased the activity at VR 1 , 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 VR 1 and AMT, but not the affinity for CB 1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR 1 and AMT but exhibited little affinity for CB 1 receptors. The urea analog was a potent FAAH inhibitor (IC 50 ϭ 2.0 M). A water-soluble analog of arvanil, O-2142, was as active on VR 1 , much less active on AMT and CB 1 , and more potent on FAAH. All compounds induced a response in the mouse "tetrad", particularly those with EC 50 Ͻ10 nM on VR 1 . However, the most potent compound, N-NЈ-di-(3-chloro-4-hydroxy)benzylarachidonamide (O-2093, ED 50 ϳ0.04 mg/kg), did not activate VR 1 or CB 1 receptors. Our findings suggest that VR 1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.

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LcrF, a Multiple Adaptational Response (MAR) transcription factor, regulates virulence in Yersinia pestis and Yersinia pseudotuberculosis. In a search for small molecule inhibitors of LcrF, an acrylic amide series of N-hydroxybenzimidazoles was synthesized, and the SAR (structure-activity relationship) was examined. Selected test compounds demonstrated inhibitory activity in a primary cell-free LcrF-DNA binding assay as well as in a secondary whole cell assay (Type III secretion system dependent Y. pseudotuberculosis cytotoxicity assay). The inhibitors exhibited no measurable antibacterial activity in vitro, confirming that they do not target bacterial growth. These results demonstrate that N-hydroxybenzimidazole inhibitors, exemplified by 14, 22 and 36, are effective anti-virulence agents, and have the potential to prevent infections caused by Yersinia spp.

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