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Activation of TRPA1 channels by the fatty acid amide hydrolase inhibitor 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597).
Mol Pharmacol. 2007 May; 71(5):1209-16.MP

Abstract

As a member of the transient receptor potential (TRP) ion channel superfamily, the ligand-gated ion channel TRPA1 has been implicated in nociceptive function and pain states. The endogenous ligands that activate TRPA1 remain unknown. However, various agonists have been identified, including environmental irritants (e.g., acrolein) and ingredients of pungent natural products [e.g., allyl isothiocyanate (ITC), cinnamaldehyde, allicin, and gingerol]. In general, these agents are either highly reactive, nonselective, or not potent or efficacious, significantly limiting their utilities in the study of TRPA1 channel properties and biological functions. In a search for novel TRPA1 agonists, we identified 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597), a potent and systemically active inhibitor of fatty acid amide hydrolase (FAAH). This enzyme is responsible for anandamide degradation and therefore has been pursued as an antinociceptive and antiepileptic drug target. Using Ca(2+) influx assays and patch-clamp techniques, we demonstrated that URB597 could activate heterologously expressed human and rat TRPA1 channels, whereas two other FAAH inhibitors (i.e., URB532 and Compound 7) had no effect. When applied to inside-out membrane patches expressing rat TRPA1, URB597 elicited single-channel activities with a unitary conductance of 40 pS. Furthermore, URB597 activated TRPA1 channels endogenously expressed in a population of rat dorsal root ganglion neurons that also responded to ITC. In contrast to its effect on TRPA1, URB597 inhibited TRPM8 and had no effects on TRPV1 or TRPV4. Thus, we conclude that URB597 is a novel agonist of TRPA1 and probably activates the channel through a direct gating mechanism.

Authors+Show Affiliations

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6125, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17314320

Citation

Niforatos, Wende, et al. "Activation of TRPA1 Channels By the Fatty Acid Amide Hydrolase Inhibitor 3'-carbamoylbiphenyl-3-yl Cyclohexylcarbamate (URB597)." Molecular Pharmacology, vol. 71, no. 5, 2007, pp. 1209-16.
Niforatos W, Zhang XF, Lake MR, et al. Activation of TRPA1 channels by the fatty acid amide hydrolase inhibitor 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597). Mol Pharmacol. 2007;71(5):1209-16.
Niforatos, W., Zhang, X. F., Lake, M. R., Walter, K. A., Neelands, T., Holzman, T. F., Scott, V. E., Faltynek, C. R., Moreland, R. B., & Chen, J. (2007). Activation of TRPA1 channels by the fatty acid amide hydrolase inhibitor 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597). Molecular Pharmacology, 71(5), 1209-16.
Niforatos W, et al. Activation of TRPA1 Channels By the Fatty Acid Amide Hydrolase Inhibitor 3'-carbamoylbiphenyl-3-yl Cyclohexylcarbamate (URB597). Mol Pharmacol. 2007;71(5):1209-16. PubMed PMID: 17314320.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of TRPA1 channels by the fatty acid amide hydrolase inhibitor 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597). AU - Niforatos,Wende, AU - Zhang,Xu-Feng, AU - Lake,Marc R, AU - Walter,Karl A, AU - Neelands,Torben, AU - Holzman,Thomas F, AU - Scott,Victoria E, AU - Faltynek,Connie R, AU - Moreland,Robert B, AU - Chen,Jun, Y1 - 2007/02/21/ PY - 2007/2/23/pubmed PY - 2007/5/30/medline PY - 2007/2/23/entrez SP - 1209 EP - 16 JF - Molecular pharmacology JO - Mol Pharmacol VL - 71 IS - 5 N2 - As a member of the transient receptor potential (TRP) ion channel superfamily, the ligand-gated ion channel TRPA1 has been implicated in nociceptive function and pain states. The endogenous ligands that activate TRPA1 remain unknown. However, various agonists have been identified, including environmental irritants (e.g., acrolein) and ingredients of pungent natural products [e.g., allyl isothiocyanate (ITC), cinnamaldehyde, allicin, and gingerol]. In general, these agents are either highly reactive, nonselective, or not potent or efficacious, significantly limiting their utilities in the study of TRPA1 channel properties and biological functions. In a search for novel TRPA1 agonists, we identified 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597), a potent and systemically active inhibitor of fatty acid amide hydrolase (FAAH). This enzyme is responsible for anandamide degradation and therefore has been pursued as an antinociceptive and antiepileptic drug target. Using Ca(2+) influx assays and patch-clamp techniques, we demonstrated that URB597 could activate heterologously expressed human and rat TRPA1 channels, whereas two other FAAH inhibitors (i.e., URB532 and Compound 7) had no effect. When applied to inside-out membrane patches expressing rat TRPA1, URB597 elicited single-channel activities with a unitary conductance of 40 pS. Furthermore, URB597 activated TRPA1 channels endogenously expressed in a population of rat dorsal root ganglion neurons that also responded to ITC. In contrast to its effect on TRPA1, URB597 inhibited TRPM8 and had no effects on TRPV1 or TRPV4. Thus, we conclude that URB597 is a novel agonist of TRPA1 and probably activates the channel through a direct gating mechanism. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/17314320/Activation_of_TRPA1_channels_by_the_fatty_acid_amide_hydrolase_inhibitor_3'_carbamoylbiphenyl_3_yl_cyclohexylcarbamate__URB597__ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17314320 DB - PRIME DP - Unbound Medicine ER -