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 -