title: The carbonate analogues of 5'-halogenated resiniferatoxin as TRPV1 ligands.
abstract: A series of carbonate analogues of 5'-halogenated RTX have been investigated in order to examine the effect of the carbonate group as a linker and the role of halogens in the reversal of activity from agonism to antagonism for rat and human TRPV1 heterologously expressed in Chinese hamster ovary cells. The carbonate analogues showed similar activities to the corresponding RTX derivatives in rat TRPV1 but lower potency in human TRPV1. 5-Halogenation converted the agonists to partial agonists or full antagonists and the extent of antagonism reflected the order of I>Br>Cl>F, with a somewhat greater extent of antagonism for the derivatives of the 4-amino RTX surrogates compared to the corresponding derivatives of RTX itself. The carbonate analogues of I-RTX (60) and 5-bromo-4-amino-RTX (66) were potent and full antagonists with Ki(ant)=2.23 and 2.46 nM, respectively, for rat TRPV1, which were ca. 5-fold more potent than I-RTX (2) under our conditions. The conformational analysis of the I-RTX-carbonate (60) indicated that its bent conformation was similar to that of I-RTX, consistent with compound 60 and I-RTX showing comparable potent antagonism.
authors: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Kwang Su
authors: KS
authors: Lim
authors: Hobin
authors: H
authors: Lee
authors: Sung Eun
authors: SE
authors: Kim
authors: Tae-Hwan
authors: TH
authors: Ha
authors: Jihyae
authors: J
authors: Ann
authors: Karam
authors: K
authors: Son
authors: Sun
authors: S
authors: Choi
authors: Wei
authors: W
authors: Sun
authors: Larry V
authors: LV
authors: Pearce
authors: Ian A
authors: IA
authors: DeAndrea-Lazarus
authors: Peter M
authors: PM
authors: Blumberg
authors: Jeewoo
authors: J
authors: Lee
mesh_terms: D000818:Animals; D016466:CHO Cells; D002254:Carbonates / Q000737:chemistry* / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D050916:TRPV Cation Channels / Q000819:agonists*
chemical_list: D002254:Carbonates; D004224:Diterpenes; D006219:Halogens; D008024:Ligands; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C024353:resiniferatoxin
keywords: Halogenation; Molecular modelling; Partial agonist; Resiniferatoxin; TRPV1 agonist; TRPV1 antagonist
references: Br J Pharmacol. 1999 Sep;128(2):428-34
references: 10510454
references: Bioorg Med Chem Lett. 2010 Jan 1;20(1):97-9
references: 19951840
references: J Med Chem. 1996 Jul 19;39(15):2939-52
references: 8709128
references: Neuroscience. 1989;30(2):515-20
references: 2747924
references: Life Sci. 1997;60(10):681-96
references: 9064473
references: Anesthesiology. 2005 Nov;103(5):1052-9
references: 16249680
references: Brain Res. 1998 Nov 2;809(2):246-52
references: 9853117
references: J Neurochem. 1995 Jul;65(1):301-18
references: 7790875
references: Mol Pharmacol. 2002 Oct;62(4):947-56
references: 12237342
references: Mol Pharmacol. 2004 Feb;65(2):282-91
references: 14742669
references: Bioorg Med Chem. 2009 Jan 15;17(2):690-8
references: 19135377
references: J Investig Dermatol Symp Proc. 1997 Aug;2(1):56-60
references: 9487017
references: Bioorg Med Chem Lett. 2002 Apr 22;12(8):1189-92
references: 11934585
references: Expert Opin Investig Drugs. 2004 Nov;13(11):1445-56
references: 15500392
references: Brain Res Mol Brain Res. 1996 Jan;35(1-2):173-82
references: 8717353
references: Bioorg Med Chem Lett. 2011 Jan 1;21(1):299-302
references: 21111618
references: J Med Chem. 1996 Aug 2;39(16):3123-31
references: 8759633
references: Curr Top Med Chem. 2011;11(17):2159-70
references: 21671878
references: J Pharmacol Exp Ther. 2002 Dec;303(3):1052-60
references: 12438527
references: J Nat Prod. 1982 May-Jun;45(3):347-54
references: 7119808
references: Curr Top Med Chem. 2011;11(17):2171-9
references: 21671877
references: Brain Res. 1989 Nov 27;503(1):68-72
references: 2611660
references: Bioorg Med Chem Lett. 2007 Jan 1;17(1):132-5
references: 17046253
references: Mol Pharmacol. 2001 Jan;59(1):9-15
references: 11125018