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, 68, 233-43

The Carbonate Analogues of 5'-halogenated Resiniferatoxin as TRPV1 Ligands

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The Carbonate Analogues of 5'-halogenated Resiniferatoxin as TRPV1 Ligands

Kwang Su Lim et al. Eur J Med Chem.

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.

Keywords: Halogenation; Molecular modelling; Partial agonist; Resiniferatoxin; TRPV1 agonist; TRPV1 antagonist.

Figures

Fig. 1.
Fig. 1.
Resiniferatoxin and its carbonate analogs.
Fig. 2.
Fig. 2.
The lowest energy conformers of (A) RTX and (B) I-RTX superimposed with I-RTX-carbonate. Carbon atoms are shown in green for RTX, white for I-RTX, and magenta for I-RTX-carbonate. RTX and I-RTX are depicted as capped stick. I-RTX-carbonate is in ball-and-stick. Hydrogen bonds are displayed in black dashed lines, and non-polar hydrogens are undisplayed for clarity.
Scheme 1.
Scheme 1.
Reactions and conditions: (a) i) 37% formaldehyde, 40% NMe2, reflux, 2 h, ii) MeI, CHCl3, rt, 18 h, iii) ACOH/H2O, HMTA, HCl, 120 °C, 2 h; (b) X = Cl: NCS, NaH, THF, 0 °C to rt, overnight; (c) TBS-Cl, NEt3, DMAP, CH2Cl2, 0 °C, 2 h; (d) m-CPBA, CH2Cl2, rt, overnight; (e) K2CO3, MeOH, rt, overnight.
Scheme 2.
Scheme 2.
Reactions and conditions: (a) MeI, K2CO3, acetone, reflux, 3 h; (b) NaOH, H2O, DMSO, rt, overnight; (c) Ac2O, pyridine, THF, rt, 5 h; (d) 10% Pd/C, H2, MeOH/THF, rt, 1 h; (e) Boc2O, NaHCO3, H2O/THF, 0 °C-rt, overnight; (f) NaHCO3, H2O, MeOH, rt, 48 h; (g) MsCl, pyridine.
Scheme 3.
Scheme 3.
Reactions and conditions: (a) HNO3, CH2Cl2, 0 °C to rt, overnight; (b) MOM-Cl, DIPEA, CH2Cl2, 0 °C to rt, overnight; (c) NaOMe, MeOH, rt, 8 h; (d) Pd/C, H2, THF–EtOH, overnight; (e) CF3CO2H, CH2Cl2, rt, 3 h; (f) NH3 in MeOH, rt, 2 days; (g) X = Cl: t-BuONO, Cu(II)Cl2, CH3CN, 0 °C to rt,1 h, X = Br: t-BuONO, Cu(I)Br, CH3CN, rt,1 h, 65 °C, 3 h, X = I: t-BuONO, I2, CH3CN, 60 °C, 2 h, rt, overnight; (h) hydrazine hydrate, FeCl3─6H2O, carbon, MeOH, 65 °C, reflux, 1–10 h.
Scheme 4.
Scheme 4.
Reactions and conditions: (a)4-nitrophenyl chloroformate, NEt3, CH2Cl2, 0 °C to rt, overnight; (b) R─OH, CH2Cl2, rt, overnight; (c)TBAF, THF, rt; (d) CF3CO2H, CH2Cl2, 0 °C.

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