Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin

Article abstract of DOI:10.1016/j.bmcl.2006.09.059

Selected potent TRPV1 agonists (1-6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I > Br > Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with K_i (as functional antagonist) = 23.1 and 30.3 nM in rTRPV1/CHO system, respectively.

Full text of DOI:10.1016/j.bmcl.2006.09.059

Bioorganic & Medicinal Chemistry Letters 17 (2007) 214–219
Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1
agonists showed enhanced antagonism to capsaicin
Dong Wook Kang,a HyungChul Ryu,a Jeewoo Lee,a,* Krystle A. Lang,b
Vladimir A. Pavlyukovets,b Larry V. Pearce,b Tetsurou Ikeda,b
Jozsef Lazarb and Peter M. Blumbergb
aResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
bLaboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute,
NIH, Bethesda, MD 20892, USA
Received 22 August 2006; accepted 20 September 2006
Available online 10 October 2006
Abstract—Selected potent TRPV1 agonists (1–6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze
their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at
TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as
the size of the halogen increased (I > Br > Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to
be potent full antagonists with Ki (as functional antagonist) = 23.1 and 30.3 nM in rTRPV1/CHO system, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.
TRPV1 is a member of the transient receptor potential
(TRP) superfamily;1 the TRP family proteins form
non-voltage activated cation channels and share a struc-
tural characteristic of six transmembrane segments.2,3
TRPV1 functions as a molecular integrator of nocicep-
tive stimuli expressed predominantly on unmyelinated
pain-sensing nerve fibers (C-fibers) and small Ad fibers
in the dorsal root, trigeminal, and nodose ganglia. It is
activated by protons,4 heat,5 endogenous substances
such as anandamide6 and lipoxygenase products,7 by
vanilloids such as capsaicin (CAP)8 and resiniferatoxin
(RTX),9 or indirectly by bradykinin.10 Since TRPV1 is
a non-selective cation channel with high Ca2+ perme-
ability, its activation by these agents leads to an increase
in intracellular Ca2+ that results in excitation of the pri-
mary sensory neurons (Fig. 1).
pathic pain, cystitis, and bladder hyperreflexia. TRPV1
antagonists have attracted much attention so far as
promising drug candidates to inhibit the transmission
of painful signals from the periphery to the CNS and
to block other pathological states associated with this
receptor. A therapeutic advantage of TRPV1 antago-
nism over agonism is that it lacks the initial excitatory
effect preceding the desensitization. The initial acute
pain associated with capsaicin treatment has proven to
be the limiting toxicity. A further advantage of antago-
nists is that their effects are readily reversible (Fig. 2).
Previously, we have demonstrated that so-called simpli-
fied RTX analogues, N-(3-pivaloyloxy-2-benzylpropyl)-
N0-(4-hydroxy-3-methoxybenzyl)thioureas (1 and 2),11
N-[2-pivaloyloxy-1-(phenethyl)ethyl]-N0-(4-hydroxy-3-
methoxybenzyl)thioureas (3 and 4),12 and N-[2-pivaloyl-
oxy-1-(4-t-butylbenzyl)ethyl]-N0-(4-hydroxy-3-meth-
oxybenzyl)thiourea (5),12 possess potent TRPV1
agonism with high affinity, having a range of Ki (bind-
ing) = 6.35–56 nM and EC50 (agonism) = 1.97–21.5 nM
in rat TRPV1 heterologously expressed in Chinese ham-
ster ovary (CHO) cells and excellent analgesic activities.
N-(4-t-Butylbenzyl)-N0-(4-hydroxy-3-methoxybenzyl)
thiourea (6) also proved to be a highly potent agonist by
the Novartis group13 and by us.14 Interestingly, we have
found that isosteric replacement of the phenolic hydrox-
The receptor activation can be blocked either by desen-
sitization subsequent to agonist exposure or by direct
antagonism. Both strategies would have considerable
therapeutic utility targeting inflammatory and neuro-
Keywords: TRPV1 agonist; TRPV1 antagonist; Halogenation; Resi-
niferatoxin; Capsaicinoid.
*
Corresponding author. Tel.: +82 2 880 7846; fax: +82 2 888 0649;
e-mail: jeewoo@snu.ac.kr
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.09.059

D. W. Kang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 214–219
215
R
OCH3
R
OH
S
H
H
O
OCH3
OH
O
N
N
N
N
H
H
O
O
S
3 R = 4-tBu
1 R = 4-tBu
4 R = 3,4-Me2
2 R = 3,4-Me2
S
S
OCH3
OH
N
N
O
OCH3
OH
N
H
N
H
H
H
O
5
6
Figure 1.
O
O
H
O
OCH3
O
H
OH
OCH3
OH
O
N
H
OH
O
O
I
I
8
7
Figure 2.
yl group in lead agonists with the methylsulfonamido
group provided a series of antagonists effective against
the action of capsaicin. Among them, the 3-fluoro-4-
methylsulfonylamino analogue of the A-region in ago-
nists 2 and 6 showed excellent antagonism with values
of Ki (ant) = 7.8 and 9.16 nM, respectively.14,15
and nonivamide, which showed potent antagonism
with a Ki = 5.8 nM in the rTRPV1/HEK293 system
and an IC50 = 10 nM in the hTRPV1/HEK293 system,
respectively. The result prompted us to investigate
how the halogenation on the aromatic A-region of
our potent agonists modulates their functional
activity.
Recently it was reported that the halogenation of the
aromatic A-ring of agonists also shifted the agonism
of the ligands toward antagonism. Two leading exam-
ples are 5-iodoresiniferatoxin (7)16 and 6-iodononiva-
mide (8),17 iodinated products of the agonists RTX
In the present study, we describe the syntheses, receptor
activities, and the analysis of structure–activity relation-
ships of 5- and 6-halogenated analogues of our lead
agonists (1–6).
O
O
O
X
X
H
H
H
c
a
b
OH
OCH3
OMOM
OCH3
11
OH
OCH3
9
10
a: X=Cl, b: X=Br, c: X=I
X
X
X
N3
HO
SCN
d
e or f
OMOM
OCH3
13
OMOM
OCH3
12
OMOM
OCH3
14
Scheme 1. Reagents and conditions: (a) NCS, NaH, THF, 78% for X = Cl; Br2, CH2Cl2, 91% for X = Br; H3BO3, 1 N NaOH, KI, I2, H2O, 50% for
X = I; (b) MOMCl, DBU, DMF, 75% for X = Cl; MOMCl, NEt3, CH2Cl2, 92% for X = Br, 91% for X = I; (c) NaBH4, LiCl, THF–EtOH, 93–99%;
(d) DPPA, DBU, toluene, 90–99%; (e) CS2, PPh3, THF, 83% for X = Cl; (f) i—PPh3, H2O, THF, 71–96%; ii—TDI, NEt3, DMF, 50% for X = Br,
46% for X = I.

216
D. W. Kang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 214–219
O
O
AcO
H
H
a
d
b, c
OMOM
OCH3
OH
OCH3
OMOM
OCH3
9
15
16
X
X
X
AcO
N3
SCN
g
e, f
OMOM
OMOM
OMOM
OCH3
OCH3
OCH3
17
18
19
Scheme 2. Reagents and conditions: (a) MOMCl, NEt3, CH2Cl2, 98%; (b) NaBH4, LiCl, THF–EtOH; (c) Ac2O, pyridine, 99% in 2 steps; (d) oxone,
NaCl, acetone–H2O, 81% for X = Cl; oxone, NaBr, acetone–H2O, 88% for X = Br; CF3CO2Ag, I2, CH2Cl2, 87% for X = I; (e) LiOH, THF–H2O; (f)
DPPA, DBU, toluene, 63–77% in 2 steps; (g) CS2, PPh3, THF, 86–91%.
The target halogenated thiourea compounds (20–31)
were synthesized in general by the coupling of the corre-
sponding isothiocyanates with the C-region amines
reported previously. 5- or 6-halogenated isothiocyanates
of vanillin were prepared employing the two different
regioselective halogenation strategies in which the
presence of a free phenolic hydroxyl directed halogena-
tion to the 5-position and the protection of the 4-hy-
droxyl switched the regiochemistry of halogenation
from the 5-position to the 6-position.
lowed by acid hydrolysis of the protecting MOM group
provided the final halogenated thioureas (20–31) in high
yields as represented in Scheme 3.
The binding affinities and agonistic/antagonistic activ-
ities of the synthesized TRPV1 ligands were assessed
in vitro by
a
binding competition assay with
[3H]RTX and a functional 45Ca2+ uptake assay using
rat TRPV1 heterologously expressed in Chinese ham-
ster ovary (CHO) cells, as previously described.18
The results are summarized in Tables 1–4, together
with the potencies of capsazepine and the agonists
1–6. 60-Iodononivamide (8),17 previously reported as
the most potent antagonist in a series of nonivamides,
was also evaluated as a reference and displayed a full
antagonism with Ki (binding) = 1320 nM and Ki
(ant) = 127 nM, respectively.
The syntheses of 5-halogenated isothiocyanates are out-
lined in Scheme 1. Starting from commercially available
vanillin, the ortho carbon to the 4-hydroxyl was readily
halogenated and then the hydroxyl group was protected
with the methoxymethyl (MOM) group to provide 11.
The aldehyde 11 was reduced and then converted to
the corresponding azide 13, which was transformed to
the corresponding isothiocyanate 14 using carbon disul-
fide and triphenylphosphine in a step.
Our previous finding indicated that compounds 1 and 2,
N-(3-pivaloyloxy-2-benzylpropyl)-N0-(4-hydroxy-3-
methoxybenzyl)thioureas, were potent high affinity
TRPV1 agonists with EC50 (agonism) = 2.83 and
1.97 nM and Ki (binding) = 6.35 and 17.4 nM, respec-
tively. The receptor activities of halogenated analogues
of 1 and 2 are outlined in Table 1. With agonist 1, 5-ha-
logenation on the A-region shifted the agonism to
antagonism and the extent was more enhanced as the
size of halogen increases. For example, whereas 5-chlo-
rination produced a partial antagonist 20a with 37%
antagonism, 5-bromination gave 85% antagonism and
5-iodination afforded a full antagonist 20c with Ki
(ant) = 103 nM. Interestingly, 6-halogenation shifted
the agonism to antagonism further compared to 5-halo-
The syntheses of 6-halogenated analogues are shown in
Scheme 2. First, the 4-hydroxyl of vanillin was protected
with the methoxymethyl (MOM) group and then the
benzaldehyde was converted to the O-acetyl benzyl alco-
hol 16. O-Protected 16 was halogenated regioselectively
on 6-position by known methods17 and then the acet-
oxymethyl group was changed to the corresponding
isothiocyanates using a route similar to that described
in Scheme 1.
Finally, the coupling of the isothiocyantes (14 and 19)
with the corresponding amines of the C-region11,12 fol-
S
R
OCH3
OCH3
a, b
N
N
SCN
H
H
R6
OH
R6
OMOM
R5
R5
14 R5=halogens
19 R6=halogens
20-31
Scheme 3. Reagents and conditions: (a) R–NH2, 50–98%; (b) CF3CO2H, CH2Cl2 (1:2), 60–96%.

D. W. Kang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 214–219
217
Table 1.
OCH3
R
OH
H
H
O
N
N
R5
O
S
R6
Compound
R
R5
R6
H
Ki (nM) binding affinity
EC50 (nM) agonisma
Ki (nM) antagonismb
CZP
8
1300
NE
NE
520
127 29
NE
1320 120
6.35 0.48
21.3 2.7
18.8 6.3
45 15
1
4-t-Bu
4-t-Bu
H
Cl
Br
I
2.83 0.55
(49%)
(9%)
20a
20b
20c
21a
21b
21c
2
(37%)
(85%)
103 14
(71%)
55 18
71 34
NE
4-t-Bu
4-t-Bu
NE
4-t-Bu
4-t-Bu
4-t-Bu
Cl
Br
I
12.2 2.6
12.8 2.1
13.3 3.6
17.4 4.1
30.9 2.2
33.1 4.4
232 63
(24%)
NE
NE
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
H
Cl
Br
I
H
1.97 0.56
(93%)
(29%)
NE
22a
22b
22c
23a
23b
23c
NE
(70%)
121 30
(41%)
(91%)
23.1 8.0
Cl
Br
I
24.2 7.1
19.9 5.1
18.9 2.6
(63%)
(13%)
NE
Values represent means SEM from three or more experiments.
a The values in parentheses indicate the percentage of maximal calcium uptake compared with that induced by 300 nM capsaicin.
b The values in parentheses indicate the extent of partial antagonism.
Table 2.
R
S
O
OCH3
OH
N
N
H
H
O
R6
R5
Compound
R
R5
R6
H
Ki (nM) binding affinity
EC50 (nM) agonisma
Ki (nM) antagonismb
3
4-t-Bu
4-t-Bu
H
Cl
Br
I
36.5 2.6
122 21
143 48
214 35
79 15
21.5 4.1
(44%)
(19%)
NE
NE
(47%)
(73%)
24a
24b
24c
25a
25b
25c
4
4-t-Bu
4-t-Bu
525 130
72.2 7.0
76.1 7.2
69 13
NE
4-t-Bu
4-t-Bu
4-t-Bu
Cl
Br
I
NE
NE
75 13
79
7
NE
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
H
Cl
Br
I
H
56 23
86 12
14.7 2.1
(88%)
(50%)
NE
26a
26b
26c
27a
27b
27c
(16%)
(59%)
102 11
127 26
103 18
115 31
(45%)
(75%)
Cl
Br
I
(60%)
(13%)
NE
109
140 20
7
176 21
Values represent means SEM from three or more experiments.
a The values in parentheses indicate the percentage of maximal calcium uptake compared with that induced by 300 nM capsaicin.
b The values in parentheses indicate the extent of partial antagonism.
genation. Indeed, 6-chlorination of 1 was able to exert
71% antagonism, and 6-bromination and 6-iodination
provided full antagonists 21b and 21c with Ki
(ant) = 55 and 71 nM, respectively.
A similar SAR pattern was observed in the halogenated
analogues of agonist 2, Both 5- and 6-halogenation
shifted the agonism to antagonism with the order of
I > Br > Cl and 6-halogenation produced more en-

218
D. W. Kang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 214–219
Table 3.
S
O
OCH3
OH
N
N
H
H
O
R6
R5
Compound
R5
R6
H
Ki (nM) binding affinity
EC50 (nM) agonisma
Ki (nM) antagonismb
5
H
Cl
Br
I
34.6 9.6
28.8 5.3
38.2 6.8
39.4 6.1
41.5 1.4
74.9 3.7
96 10
5.7 2.1
60 18
(57%)
NE
NE
NE
28a
28b
28c
29a
29b
29c
(29%)
178 72
(11%)
(51%)
310 100
Cl
Br
I
(94%)
(41%)
NE
Values represent means SEM from three or more experiments.
a The values in parentheses indicate the percentage of maximal calcium uptake compared with that induced by 300 nM capsaicin.
b The values in parentheses indicate the extent of partial antagonism.
Table 4.
OCH3
OH
H
H
N
N
R5
S
R6
Compound
R5
R6
H
Ki (nM) binding affinity
EC50 (nM) agonisma
Ki (nM) antagonismb
6
H
Cl
Br
I
58.6 9.0
76.0 13
51.6 6.7
342 97
36.9 3.5
42.1 3.5
130 16
2.5 1.1
(5%)
NE
NE
(92%)
30a
30b
30c
31a
31b
31c
49 12
176 27
(81%)
NE
Cl
Br
I
(33%)
NE
NE
30.3 6.3
156 58
Values represent means SEM from three or more experiments.
a The values in parentheses indicate the percentage of maximal calcium uptake compared with that induced by 300 nM capsaicin.
b The values in parentheses indicate the extent of partial antagonism.
hanced antagonism. On the result, 6-iodination of ago-
nist 2 led to very potent antagonist 23c with Ki
(ant) = 23.1 nM, which was 5.5-fold and 20-fold more
potent than 6-iodononivamide (8) and capsazepine,
respectively. All halogenated analogues (20–23) dis-
played comparable or slightly less binding affinities com-
pared to the parent compound (1 and 2) except
compound 22c.
found to be full antagonists with a range of Ki
(ant) = 69–76 nM.
A similar SAR pattern was observed in the halogenated
analogues of N-[2-pivaloyloxy-1-(4-tert-butylbenzyl)eth-
yl]-N0-(4-hydroxy-3-methoxybenzyl)thiourea (5) and
N-(4-tert-butylbenzyl)-N0-(4-hydroxy-3-methoxyben-
zyl)thiourea (6) as shown in Tables 3 and 4, respectively.
Among them, N-(4-tert-butylbenzyl)-N0-(6-bromo-4-hy-
droxy-3-methoxybenzyl)thiourea (31b) displayed very
potent antagonism with Ki = 30.3 nM.
The SAR of halogenated analogues of N-[2-pivaloyl-
oxy-1-(phenethyl)ethyl]-N0-(4-hydroxy-3-methoxyb-
enzyl) thiourea (3 and 4) is described in Table 2.
Similar to the results described in Table 1, the haloge-
nation of 3 and 4 also converted the agonists to
partial antagonists or full antagonists, and the antag-
onism was enhanced with the order of I > Br > Cl and
6-halogenation > 5-halogenation. In particular, all 6-
halogenated analogues of agonist 3 (25a–c) were
Previously it was established that halogenation of RTX
or capsaicinoid reverted the activity of the agonists to
generate antagonists. However, halogenated RTX and
capsainoid analogues showed different structure–activity
relationships for the reversal of activity. In the RTX ser-
ies, whereas 5-iodination produced a maximal full

D. W. Kang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 214–219
219
antagonism,16 6-iodination led to partial agonism with
50% efficacy in the hTRPV1/HEK system.19 On the
other hand, in the capsaicinoid series, although both
5- and 6-iodo derivatives behaved as powerful antago-
nists under the same assay conditions, the 6-iodo deriv-
ative was more potent than the corresponding 5-iodo
analogue. The analysis indicated that our lead agonists
(1–6) investigated in this study are more like capsaici-
noid-type ligands rather than RTX-type ligands
although the ligands were initially designed as simplified
RTX analogues.
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Acknowledgments
This work was supported by Grant R01-2004-000-
10132-0 from the Basic Research Program of the Korea
Science and Engineering Foundation and this research
was supported in part by the Intramural Research Pro-
gram of the NIH, National Cancer Institute, Center for
Cancer Research. We thank Matthew A. Morgan, An-
drew K. Tao, and Christopher B. Ryder for technical
assistance.
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