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(R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) blocks polymodal activation of transient receptor potential vanilloid 1 receptors in vitro and heat-evoked firing of spinal dorsal horn neurons in vivo.
J Pharmacol Exp Ther. 2008 Sep; 326(3):879-88.JP

Abstract

The transient receptor potential vanilloid (TRPV) 1 receptor, a nonselective cation channel expressed on peripheral sensory neurons and in the central nervous system, plays a key role in pain. TRPV1 receptor antagonism is a promising approach for pain management. In this report, we describe the pharmacological and functional characteristics of a structurally novel TRPV1 antagonist, (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102), which has entered clinical trials. At the recombinant human TRPV1 receptor ABT-102 potently (IC(50) = 5-7 nM) inhibits agonist (capsaicin, N-arachidonyl dopamine, anandamide, and proton)-evoked increases in intracellular Ca(2+) levels. ABT-102 also potently (IC(50) = 1-16 nM) inhibits capsaicin-evoked currents in rat dorsal root ganglion (DRG) neurons and currents evoked through activation of recombinant rat TRPV1 currents by capsaicin, protons, or heat. ABT-102 is a competitive antagonist (pA(2) = 8.344) of capsaicin-evoked increased intracellular Ca(2+) and shows high selectivity for blocking TRPV1 receptors over other TRP receptors and a range of other receptors, ion channels, and transporters. In functional studies, ABT-102 blocks capsaicin-evoked calcitonin gene-related peptide release from rat DRG neurons. Intraplantar administration of ABT-102 blocks heat-evoked firing of wide dynamic range and nociceptive-specific neurons in the spinal cord dorsal horn of the rat. This effect is enhanced in a rat model of inflammatory pain induced by administration of complete Freund's adjuvant. Therefore, ABT-102 potently blocks multiple modes of TRPV1 receptor activation and effectively attenuates downstream consequences of receptor activity. ABT-102 is a novel and selective TRPV1 antagonist with pharmacological and functional properties that support its advancement into clinical studies.

Authors+Show Affiliations

Abbott Laboratories, R4PM, AP9/1, 100 Abbott Park Road, Abbott Park, IL 60064-6118, USA. carol.s.surowy@abbott.comNo 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 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)

Comparative Study
Journal Article

Language

eng

PubMed ID

18515644

Citation

Surowy, Carol S., et al. "(R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) Blocks Polymodal Activation of Transient Receptor Potential Vanilloid 1 Receptors in Vitro and Heat-evoked Firing of Spinal Dorsal Horn Neurons in Vivo." The Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 3, 2008, pp. 879-88.
Surowy CS, Neelands TR, Bianchi BR, et al. (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) blocks polymodal activation of transient receptor potential vanilloid 1 receptors in vitro and heat-evoked firing of spinal dorsal horn neurons in vivo. J Pharmacol Exp Ther. 2008;326(3):879-88.
Surowy, C. S., Neelands, T. R., Bianchi, B. R., McGaraughty, S., El Kouhen, R., Han, P., Chu, K. L., McDonald, H. A., Vos, M., Niforatos, W., Bayburt, E. K., Gomtsyan, A., Lee, C. H., Honore, P., Sullivan, J. P., Jarvis, M. F., & Faltynek, C. R. (2008). (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) blocks polymodal activation of transient receptor potential vanilloid 1 receptors in vitro and heat-evoked firing of spinal dorsal horn neurons in vivo. The Journal of Pharmacology and Experimental Therapeutics, 326(3), 879-88. https://doi.org/10.1124/jpet.108.138511
Surowy CS, et al. (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) Blocks Polymodal Activation of Transient Receptor Potential Vanilloid 1 Receptors in Vitro and Heat-evoked Firing of Spinal Dorsal Horn Neurons in Vivo. J Pharmacol Exp Ther. 2008;326(3):879-88. PubMed PMID: 18515644.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) blocks polymodal activation of transient receptor potential vanilloid 1 receptors in vitro and heat-evoked firing of spinal dorsal horn neurons in vivo. AU - Surowy,Carol S, AU - Neelands,Torben R, AU - Bianchi,Bruce R, AU - McGaraughty,Steve, AU - El Kouhen,Rachid, AU - Han,Ping, AU - Chu,Katharine L, AU - McDonald,Heath A, AU - Vos,Melissa, AU - Niforatos,Wende, AU - Bayburt,Erol K, AU - Gomtsyan,Arthur, AU - Lee,Chih-Hung, AU - Honore,Prisca, AU - Sullivan,James P, AU - Jarvis,Michael F, AU - Faltynek,Connie R, Y1 - 2008/05/30/ PY - 2008/6/3/pubmed PY - 2008/9/30/medline PY - 2008/6/3/entrez SP - 879 EP - 88 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 326 IS - 3 N2 - The transient receptor potential vanilloid (TRPV) 1 receptor, a nonselective cation channel expressed on peripheral sensory neurons and in the central nervous system, plays a key role in pain. TRPV1 receptor antagonism is a promising approach for pain management. In this report, we describe the pharmacological and functional characteristics of a structurally novel TRPV1 antagonist, (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102), which has entered clinical trials. At the recombinant human TRPV1 receptor ABT-102 potently (IC(50) = 5-7 nM) inhibits agonist (capsaicin, N-arachidonyl dopamine, anandamide, and proton)-evoked increases in intracellular Ca(2+) levels. ABT-102 also potently (IC(50) = 1-16 nM) inhibits capsaicin-evoked currents in rat dorsal root ganglion (DRG) neurons and currents evoked through activation of recombinant rat TRPV1 currents by capsaicin, protons, or heat. ABT-102 is a competitive antagonist (pA(2) = 8.344) of capsaicin-evoked increased intracellular Ca(2+) and shows high selectivity for blocking TRPV1 receptors over other TRP receptors and a range of other receptors, ion channels, and transporters. In functional studies, ABT-102 blocks capsaicin-evoked calcitonin gene-related peptide release from rat DRG neurons. Intraplantar administration of ABT-102 blocks heat-evoked firing of wide dynamic range and nociceptive-specific neurons in the spinal cord dorsal horn of the rat. This effect is enhanced in a rat model of inflammatory pain induced by administration of complete Freund's adjuvant. Therefore, ABT-102 potently blocks multiple modes of TRPV1 receptor activation and effectively attenuates downstream consequences of receptor activity. ABT-102 is a novel and selective TRPV1 antagonist with pharmacological and functional properties that support its advancement into clinical studies. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/18515644/_R___5_tert_butyl_23_dihydro_1H_inden_1_yl__3__1H_indazol_4_yl__urea__ABT_102__blocks_polymodal_activation_of_transient_receptor_potential_vanilloid_1_receptors_in_vitro_and_heat_evoked_firing_of_spinal_dorsal_horn_neurons_in_vivo_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18515644 DB - PRIME DP - Unbound Medicine ER -