Anandamide transport inhibitors

ANANDAMIDE TRANSPORT INHIBITORS The Hydrophobic Chain The Carboxamide/Carboxylate Group The Polar Head Group... 

Zygmunt PM, Chuang H, Movahed P, Julius D, Hogestatt ED (2000) The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 396 39-42... 

Beltramo M, Rodriguez de Fonseca F, Navarro M, Calignano A, Gorriti MA, Grammatikopou-los G, Sadile AG, Giuffrida A, Piomelli D (2000) Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor. J Neurosci 20 3401-3407... 

Kamei J, Saitoh A, Suzuki T, Misawa M, Nagase H, Kasuya Y (1995b) Buprenorphine exerts its antinociceptive activity via mu 1-opioid receptors. Life Sci 56 PL285-290 Kamei J, Morita K, Ohsawa M, Onodera K (1999) Effects of epinastine on the antitussive and rewarding effects of dihydrocodeine in mice. Methods Lind Exp Clin Pharmacol 21 663-668 Kamei J, Morita K, Saitoh A, Nagase H (2003) The antitussive effects of endomorphin-1 and endomorphin-2 in mice, Eur J Pharmacol 467 219-222 Kamei J, Yoshikawa Y, Saitoh A (2006) Effect of A-arachidonoyl-(2-methyl-4-hydroxyphenyl) amine (VDMll), an anandamide transporter inhibitor, on capsaicin-induced cough in mice. Cough 2 2... 

A variety of synthetic compounds have been tested for their ability to interfere with endocannabinoid transport. Among them, the first reported anandamide transporter inhibitor, A-(4-hydroxyphenyl)arachidonoyl amide (AM404, Figure 7) (Beltramo et aL, 1997), stands out for its relatively high potency and its ability to block endocannabinoid transport both in vitro and in vivo, AM404... 

Anandamide is inactivated in two steps, first by transport inside the cell and subsequently by intracellular enzymatic hydrolysis. The transport of anandamide inside the cell is a carrier-mediated activity, having been shown to be a saturable, time- and temperature-dependent process that involves some protein with high affinity and specificity for anandamide (Beltramo, 1997). This transport process, unlike that of classical neurotransmitters, is Na+-independent and driven only by the concentration gradient of anandamide (Piomelli, 1998). Although the anandamide transporter protein has not been cloned yet, its well characterized activity is known to be inhibited by specific transporter inhibitors. Reuptake of 2-AG is probably mediated by the same facilitating mechanism (Di Marzo, 1999a,b Piomelli, 1999). 

Fegley, D., Kathuria, S., Mercier, R., Li, C., Goutopoulos, A., Makriyannis, A., and Piomelli, D. (2004). Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AMI 172. Proc. Natl. Acad. Sci. USA 101, 8756—8761. 

De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V (2000) Overlap between the ligand recognition properties of the anandamide transporter and the VRl vanilloid receptor inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett 483 52-56... 

Ruiz-Llorente L, Ortega- Gutierrez S, Viso A, Sdnchez MG, Sanchez AM, Fernandez C, Ramos JA, Hillard C, Lasuncidn MA, Ldpez-Rodrfguez ML, Diaz-Laviada I (2004) Characterization of an anandamide degradation system in prostate epithelial PC-3 cells synthesis of new transporter inhibitors as tools for this study. Br J Pharmacol 141 457-467... 

Substitution of the 2-hydroxyethyl group with a phenolic group results in decreased affinity for CBi (Khanolkar et al. 1996). However, N-(o-hydroxy)phenyl-arachidonamide (AM403) was found to be an excellent substrate for FAAH (Lang et al. 1999) while a second phenolic analog, N-(p-hydroxy)phcnylarachidonamide (AM404), was found to be an inhibitor for the anandamide transporter (ANT)... 

Transporter inhibitors AM404, VDMl 1,0MDM2, UCM707 Decreased ambulation and increased inactivity in rats (Gonzalez et al. 1999 Beltramo et al. 2000) Potentiated anandamide-induced motor inhibition (de Lago et al. 2002 and 2004a)... 

Despite the fact that the endocannabinoid transporter has not yet been isolated or cloned, a situation that has led to some controversy about its existence (Glaser et al. 2003), there are several anandamide analogs that behave in vitro as endocannabinoid transport inhibitors (Giuffrida et al. 2001) and that, in vivo, produce significant effects on motor function (for review see Ferndndez-Ruiz et al. 2002). 

Another approach to examining the role of endogenous anandamide in pain has been to employ transport inhibitors such as AM404. Blocking transport would be expected to block the reuptake of anandamide and cause increased levels to... 

Calignano A, La Rana G, Beltramo M, Makriyannis A, PiomeUi D (1997) Potentiation of anandamide hypotension by the transport inhibitor, AM404. Eur J Pharmacol 337 R1-R2... 

Giuffrida, A., Rodriguez de Fonseca, E, Nava, E, Loubet-Lescoulie, R, and Piomelli, D. (2000) Elevated circulating levels of anandamide after administration of the transport inhibitor, AM404, European Journal of Pharmacology 408 161-168. 

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