Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1

Article abstract of DOI:10.1016/j.bmcl.2008.08.105

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.

Full text of DOI:10.1016/j.bmcl.2008.08.105

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5609–5613
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of 6-phenylnicotinamide derivatives as antagonists
of TRPV1
a
a
a
a
Susan M. Westaway a, , Mervyn Thompson , Harshad K. Rami , Geoffrey Stemp , Leontine S. Trouw ,
Darren J. Mitchell a, Jon T. Seal a, Stephen J. Medhurst a, Sarah C. Lappin a, James Biggs a, James Wright a,
Sandra Arpino c, Jeffrey C. Jerman b, Jennifer E. Cryan c, Vicky Holland b, Kim Y. Winborn b, Tanya Coleman a,
Alexander J. Stevens a, John B. Davis a, Martin J. Gunthorpe a
*
a Neurology CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
b Molecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
c Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an
in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl
and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-meth-
ylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has
been progressed into pre-clinical development.
Received 15 July 2008
Revised 26 August 2008
Accepted 28 August 2008
Available online 31 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
TRPV1 antagonist
Vanilloid
SB-782443
The TRPV1 (transient receptor potential vanilloid type 1) ion
channel is an exciting target for the discovery of novel analgesics.
TRPV1 is a non-selective ion channel which is primarily, although
not exclusively, expressed on peripheral sensory neurons.1 Activa-
tion of TRPV1 may occur through exposure to noxious heat (>42 °C)
and low pH. Exogenous compounds such as the ‘vanilloids’ capsa-
icin and resiniferatoxin (RTX) are well-known agonists of TRPV1. A
variety of endogenous substances such as the cannabinoid ananda-
mide and inflammatory mediators such as arachidonic acid metab-
olites from the lipoxygenase pathway can also directly activate
and/or sensitise the channel to activation by other mediators.
Other substances such as inflammatory prostaglandins and brady-
kinin indirectly lead to sensitisation of TRPV1 through phosphory-
lation of the channel. Thus TRPV1 may be seen as an integrator of
many noxious stimuli which lead to the sensation of pain. Early ef-
forts in this area focused on TRPV1 agonists such as capsaicin and
RTX as analgesic agents through the desensitisation/denervation
approach and various formulations of capsaicin are either mar-
keted or are currently under development.2 However this approach
is often hindered by the pain and discomfort experienced on initial
treatment.2 More recently, there has been an explosion in the dis-
covery and development of TRPV1 antagonists for the treatment of
osteoarthritic, neuropathic, post-operative and dental pain3 and
several compounds (SB-705498, AMG-517, NGD-8243/MK-2295,
GRC-6211, AZD-1386 and ABT-102) are known to have entered
clinical trials.3,4
In an earlier letter, we reported on the SAR studies around HTS
hit (1), which led to the identification of the N-quinolin-7-yl-6-
phenylnicotinamide (2).5
O
O
HN
N
N
N
H
N
Me
1
2
This compound possessed excellent potency at human and rat
TRPV1 receptors and a favourable in vitro DMPK profile. However,
the low intrinsic clearance observed in liver microsomes (CLi 3.1
(human), 2.2 (rat), 3.9 (guinea pig) mL/min/g tissue) did not trans-
late into acceptable in vivo stability in the rat (CLb 33 mL/min/kg, T
½
* Corresponding author at present address: II CEDD, GlaxoSmithKline, Medicines
Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK. Tel.: +44 (0)
1438 763469.
0.36 h at 1 mg/kg iv). Furthermore, (2) showed only modest activity
in the guinea pig model of Freunds Complete Adjuvant (FCA)-in-
duced inflammatory pain and was less efficacious than expected
E-mail address: sue.m.westaway@gsk.com (S.M. Westaway).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.105

5610
S. M. Westaway et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5609–5613
O
O
O
(c)
(a), (b)
O
MeO
N
N
HO
N
X
N
N
N
H
N
62-64%
71-82%
Cl
Cl
X
3
4
6-7
O
(c)
97%
(b)
O
HO
N
N
H
N
N
N
35-55%
X
H
Cl
5
13
8-11
Scheme 1. Reagents and conditions: (a) ArB(OH)2, Pd(PPh3)4, Na2CO3, 1,2-DME, H2O, 80–85 °C; (b) LiOH, H2O, 1,4-dioxane, rt; (c) 7-aminoquinoline5, EDCIÁHCl, DMAP, DCM, rt.
Table 1
Table 2
Antagonist activity9 of nicotinamide derivatives
2 and 6–13 at human TRPV1
Antagonist activity9 of methylnicotinamides at human TRPV1 expressed in 1321N1
cell line7 against capsaicin (FLIPR)
expressed in a 1321N1 cell line7 against capsaicin in FLIPR (Fluoresence Imaging Plate
Reader) assay
O
R1
2
O
N
N
H
N
N
N
H
N
R2
Ar
4
R1
Compound8
R1
R2
Ar
hTRPV1a pKb
Compound8
R1
hTRPV1a pKb
17
18
22
Me
Me
H
H
H
Me
Ph
4-FPh
Ph
9.0
8.5
6.7
2
6
7
8
Ph
8.7
8.7
8.6
8.2
7.8
2-FPh
3-FPh
4-FPh
4-ClPh
4-CF3Ph
4-CNPh
4-CN
a
SEM 60.1 for (17) and (18), SEM = 0.3 for (22).
9
10
11
12
13
7.3
<6.6
<6.7
<6.7
pounds (8)–(11) were prepared directly from chloro-nicotinamide
(13) as shown in Scheme 1.
4-Cl
As illustrated in Table 1, the introduction of a fluoro-substituent
into the 2- or 3-positions, (6) and (7), was well tolerated giving
compounds with potency similar to that of the unsubstituted par-
ent (2). The 4-fluoro substituted compound (8) showed ꢀ3-fold
lower potency at TRPV1 with pKb 8.2 but following determination
of in vitro ADME properties it was found that this compound pos-
sessed the best overall in vitro profile in this series with an accept-
a
Standard error of mean (SEM) for all pKb values 60.1.
based on its high level of in vitro potency. In this letter, we report on
further optimisation of this lead series targeting, in particular, an
improved in vivo profile. This work has resulted in the identification
of a compound which showed excellent levels of activity in the gui-
nea pig FCA model on oral dosing.
able P450 inhibition profile (IC50 >10 lM at five major human
isoforms), and low intrinsic clearance in human and rat liver
microsomes (CLi 1.7 (human), 1.1 (rat) mL/min/g tissue). However,
in guinea pig microsomes, (8) proved to be a high-clearance com-
pound (CLi 42 mL/min/g). Replacement of 4-F with 4-Cl, 4-CF3 or
4-CN (9)–(11) was detrimental to potency and complete
Initial efforts focused on modification of the terminal phenyl
ring of (2). Substituted analogues (6) and (7) were prepared from
methyl 6-chloronicotinate (3) and the appropriate boronic acid
using Suzuki–Miyaura coupling conditions6 followed by hydrolysis
and standard EDCI-mediated amide coupling. Alternatively, com-
O
O
O
Me
O
Me
Me
(d)
(a)
(b), (c)
67%
Me
N
HO
N
N
N
H
N
Me
26-65%
82%
X
X
X
X=H, 14a
X=F, 14b
X=H, 15a
X=F, 15b
X=H, 16a
X=F, 16b
X=H, 17
X=F, 18
X
Cl
N
Cl
N
O
O
NC
Me
(d)
(e)
(f), (g)
91%
NC
Me
Y
N
N
N
H
N
25%
45%
Cl
Me
Me
19
20
Y=OH, 21a + Y=NH2, 21b (1.4:1)
22
Scheme 2. Reagents and conditions: (a) Dimethylformamide dimethylacetal, PhMe, 110 °C; (b) ethyl acetoacetate, NH4OAc, AcOH, 120 °C; (c) NaOH, H2O, MeOH, rt; (d)
7-aminoquinoline5, EDCIÁHCl, DMAP, DCM, rt; (e) PhB(OH)2, Pd(PPh3)4, Na2CO3, 1,2-DME, H2O, 85 °C; (f) H2, 10% Pd/C, Et3N, DMF, rt, 1 atm; (g) KOH, EtOH, H2O, rt.

S. M. Westaway et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5609–5613
5611
replacement of the terminal phenyl ring with smaller groups such
as cyano (12) or chloro (13) also resulted in reduced levels of
TRPV1 antagonist activity.
inic acid intermediates (16a) and (16b) were readily synthesised
using literature methods.10 The 4-methyl analogue (21a) was pre-
pared from the commercially available 2,6-dichoro-4-methylnico-
To investigate the effect of altering the conformation around the
biaryl amide linker, the 2- and 4-methylnicotinamide analogues
(17), (18) and (22) were prepared (Scheme 2). The 2-methylnicot-
tinonitrile (19).
A
regioselective Suzuki–Miyaura coupling
reaction followed by reductive removal of the remaining 2-chlo-
rine atom, then aqueous hydrolysis of the nitrile gave a mixture
of the desired acid (21a) and the primary amide (21b). This mix-
ture was reacted with 7-aminoquinoline5 under standard amide
coupling conditions and the unreacted amide (21b) was removed
on purification of the final product (22).
Interestingly, it was found that the presence of a methyl in the
2-position was beneficial to TRPV1 antagonist potency, compounds
(17) and (18), whereas the 4-methylnicotinamide (22) was much
less active (Table 2). The reduced potency seen with (22) may be
due to the 4-methyl group causing a conformational change result-
ing in the pyridyl nitrogen in (22) occupying an alternative and less
favourable position in the active site when compared to the
2-methyl analogue (17) and unsubstituted analogue (2).
Table 3
Antagonist activity9 of 2-methyl-6-(4-fluorophenyl)nicotinamides at human TRPV1
expressed in a 1321N1 cell line7 against capsaicin (FLIPR)
Me
O
Het
N
H
N
F
Compound8
Het
hTRPV1a pKb
The 2-methylnicotinamide (18) was tested in a guinea pig mod-
el of FCA-induced inflammatory pain11 and showed 42% reversal of
hyperalgesia at a dose of 5 mg/kg ip. Although this represented a
significant improvement over the activity of (2) in the same
in vivo model (32% reversal at 30 mg/kg sc), the P450 profile of
(18) was not ideal with the IC50 value for inhibition of CYP 3A4
23
<6.5
N
Me
N
24
25
26
27
28
7.5
6.9
7.2
6.7
6.0
N
being less than our preferred target of higher than 10 lM.
H
A series of [5,6] heterocyclic analogues was then evaluated as
alternatives to the quinoline. Compounds (23)–(34) were pre-
pared in acceptable yield by standard EDCI-mediated amide cou-
Me
N
pling of acid (16b) to
a
range of amines.12 Many of the
N
H
compounds showed interesting levels of antagonist activity
(Table 3) although potency in this series was reduced by at least
10-fold compared to that seen in the quinoline series. Indazole
(24) gave acceptable potency at TRPV1 but showed significant
inhibition of a number of P450 isoforms. In an attempt to im-
prove the P450 profile of (24), a methyl group was introduced
into the 3-position of the indazole, (25) but, unfortunately this
resulted in reduced TRPV1 potency. This same trend for reduc-
tion in TRPV1 potency on introduction of methyl substituents
was also seen in the benzimidazole series of compounds (26)–
(28). The importance of the position of the heterocyclic nitrogen
atom was demonstrated by the results observed with benzoxaz-
ole (29) and benzothiazoles (30)–(32); the 6-substituted benzox-
azole (29) and benzothiazole (30) were considerably less active
than the corresponding 5-substituted benzothiazoles (31) and
(32). The introduction of more polar functionality onto the
benzothiazole was also not well tolerated (33) and (34).
N
N
H
N
N
Me
N
Me
Me
N
H
N
O
29
30
31
<6.7
6.7
The benzothiazole analogue (32) was of particular interest as
it combined both acceptable potency and an attractive in vitro
N
S
S
N
Table 4
7.5
Antagonist activity of (32) at human, rat and guinea pig TRPV1 expressed in a HEK293
cell line7 against capsaicin and acid (pH 5.3) (FLIPR)
S
O
Me
S
N
Me
Me
N
32
33
7.4
N
N
H
S
32
F
<6.7
N
Me2N
Me2N
Agonist
TRPV1 potencya
Guinea pig
Human
Rat
S
N
Capsaicin pKb
Acid (pH 5.3) pIC50
7.2
7.4
7.4
7.2
7.0
7.0
34
<5.8
a
Data given are pKb against capsaicin activation (n = 6) and functional pIC50
against acid activation (n = 3). SEM for all data 60.1.
a
SEM 60.1 for all compounds.

5612
S. M. Westaway et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5609–5613
32
Compound
(1 µM )
1 µM Capsaicin
C
100
A
Capsaicin
pH 5.3
80
100 pA
60
2 s
32
Compound
(100 nM)
pH 5.3
40
B
20
50 pA
0
1E-10
1E-9
1E-8
1E-7
1E-6
1E-5
2 s
[Compound 32] (M)
Figure 1. Inhibition of human TRPV1 receptors by (32). Whole-cell patch-clamp recordings were made from HEK293 cells expressing hTRPV1. (A) Capsaicin-gated hTRPV1-
mediated currents (grey bar) were inhibited by co-application of 1 M (32) (white bar; 100 2% inhibition; n = 7). (B) Acid-mediated activation of hTRPV1 was achieved by
l
the application of an extracellular solution of reduced pH (pH 5.3, grey bar). Note that the response shown contains a fast desensitising ASIC (acid-sensing ion channel)
response followed by a sustained TRPV1 response.17 Subsequent co-application of 100 nM (32) (white bar) caused inhibition of the TRPV1 acid-gated current (96 5% block,
n = 4). (C) Pooled data (n = 3–7) were used to define the concentration–response relationship for the effects of (32) versus both capsaicin and acid yielding IC50s of 49 5 and
9
2 nM, respectively.
50 °C
A
B
100
80
60
40
20
0
+ 1 μM
Compound 32
Control,
Wash
200 pA
+ 1 μM
Compound 32
Control
Wash
500 ms
Figure 2. Inhibition of the heat-mediated activation of human TRPV1 receptors by (32). (A) Whole-cell currents evoked by noxious heat (50 °C, applied for the duration
indicated by the bar) were recorded from hTRPV1-expressing HEK293 cells using the patch-clamp technique. The dotted line indicates the level of non-specific background
currents that were subtracted before calculation of the degree of blockade. (B) Heat-activated currents were reversibly inhibited by 1 lM (32) (87 3% inhibition relative to
control, n = 3).
DMPK profile [CLi 2.2 (human), 4.4 (rat), 2.7 (guinea pig) mL/
min/g tissue; P450 IC50 >18 M at five major human isoforms,
with an IC50 of 9 2 nM (Fig. 1B and C). The activity of (32) was
also confirmed versus heat-mediated activation of TRPV1 where
l
all data n = 4]. Comparison of the antagonist activity of (32)
against both capsaicin- and acid (pH 5.3)-induced activation at
human, rat and guinea pig TRPV1 receptors expressed in a
HEK293 cell line revealed that (32) possessed similar levels of
potency across species, Table 4.
The antagonistic properties of (32) at hTRPV1 were also as-
sessed using patch-clamp electrophysiology.7,13 Compound (32)
gave an IC50 of 49 5 nM versus capsaicin activation (Fig. 1A and
C), in good agreement with its effect in the FLIPR. Further experi-
ments demonstrated that (32) was also a potent and reversible
antagonist of the acid (pH 5.3)-mediated activation of the receptor
it showed 87 3% inhibition at a concentration of 1 lM (Fig. 2).
These data confirm the multi-modal nature of this antagonist
and interestingly, showed enhanced potency of (32) versus the
acid-mediated activation of the receptor.
The requirement for TRPV1 antagonists to show activity against
multiple modes of activation of the channel in order to possess
in vivo pain model activity has been discussed in literature11,14
and our results from testing of (32) are consistent with this
hypothesis. On dosing at 5 mg/kg ip in the guinea pig model of
FCA-induced inflammatory pain, (32) showed 48% reversal of
mechanical hyperalgesia.

S. M. Westaway et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5609–5613
5613
A
100
B
400
300
200
100
0
***
75
50
***
***
*
ED50 @1h-0.53mg/kg
(95% conf. limits:0.11- 2.55)
25
veh
0.1
0.3
1
3
0
0.01
0.1
1
10
Dose of 32 (mg/kg)
Log dose of 32 (mg/kg)
Pre FCA reading
Post FCA reading
*P<0.05, ***P<0.001 Analysis of variance with post hoc comparison
made with LSD test comparing to vehicle response (-1 4% reversal)
1hour post compound reading
Figure 3. Effects of oral doses of compound (32) in the guinea pig model of FCA-induced inflammatory pain. (A) Paw withdrawal thresholds 1-h post-dose of compound (32).
(B) Dose–response curve showing ED50 = 0.53 mg/kg.
Wetter, J. M.; Sullivan, J. P.; Jarvis, M. F.; Faltynek, C. R.; Lee, C.-H. J. Med. Chem.
2008, 51, 392.
ability in the guinea pig (Fpo 24%), therefore a full dose–response
5. Westaway, S. M.; Chung, Y-K.; Davis, J. B.; Holland, V.; Jerman, J. C.; Medhurst,
In addition, (32) possessed an acceptable level of oral bioavail-
experiment in the FCA model with oral administration was under-
taken. As shown in Figure 3, (32) gave an excellent response with
an ED50 of 0.53 mg/kg and maximum reversal of 68 9%, when as-
sessed 1 h post-dose.
In summary, further lead optimisation around N-quinolinyl nic-
otinamide (2) has led to the development of benzothiazolyl ana-
logue (32), SB-782443.15 The combination of the attractive
in vitro activity, selectivity16 and DMPK profiles of SB-782443 with
a highly promising level of oral activity in an in vivo disease model
of inflammatory pain has resulted in the progression of SB-782443
into pre-clinical development.
S. J.; Rami, H. K.; Stemp, G.; Stevens, A. J.; Thompson, M.; Winborn, K. Y.;
Wright, J. Bioorg. Med. Chem. Lett. 2006, 16, 4553.
6. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
7. Gunthorpe, M. J.; Rami, H. K.; Jerman, J. C.; Smart, D.; Gill, C. H.; Soffin, E. M.;
Luis, H. S.; Lappin, S. C.; Egerton, J.; Smith, G. D.; Worby, A.; Howett, L.; Owen, D.;
Nasir, S.; Davies, C. H.; Thompson, M.; Wyman, P. A.; Randall, A. D.; Davis, J. B.
Neuropharmacology 2004, 46, 133.
1
8. All new compounds gave satisfactory H NMR and/or LC–MS data.
9. pKb = functional potency of a competitive antagonist (also known as functional
pKi or fpKi). Mean pKb values from at least three experiments (n) in all cases
except: compounds 23, 25 and 30 where n = 2.
10. The corresponding ethyl esters of (16a) and (16b) were prepared using
methods similar to those described in Al-Saleh, B.; Abdelkhalik, M. M.;
Eltoukhy, Afaf M.; Elnagdi, M. H. J. Heterocycl. Chem. 2002, 39, 1035.
11. Walker, K. M.; Urban, L.; Medhurst, S. J.; Patel, S.; Panesar, M.; Fox, A. J.;
McIntyre, P. J. Pharmacol. Exp. Ther. 2003, 304, 56.
12. Macdonald, G. J.; Mitchell, D. J.; Rami, H. K.; Trouw, L. S.; Thompson, M.;
Westaway, S. M. PCT Int. Appl. WO2004/072069.
References and notes
13. Rami, H. K.; Thompson, M.; Wyman, P.; Jerman, J. C.; Egerton, J.; Brough, S.;
Stevens, A. J.; Randall, A. D.; Smart, D.; Gunthorpe, M. J.; Davis, J. B. Bioorg. Med.
Chem. Lett. 2004, 14, 3631.
14. Gavva, N. R.; Tamir, R.; Klionsky, L.; Norman, M. H.; Louis, J.-C.; Wild, K. D.;
Treanor, J. J. S. Mol. Pharmacol. 2005, 68, 1524.
1. (a) Caterina, M. J.; Schumacher, M. A.; Tominaga, M.; Rosen, T. A.; Levine, J. D.;
Julius, D. Nature 1997, 389, 816; (b) Szallasi, A.; Blumberg, P. M. Pharmacol. Rev.
1999, 51, 159; (c) Cortright, D. N.; Szallasi, A. Eur. J. Biochem. 2004, 271, 1814.
2. Bley, K. R. Expert Opin. Invest. Drugs 2004, 13, 1445.
15. Characterising data for (32): 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.67 (1H,
s), 8.42 (1H, d, J 2.0 Hz), 8.22 (2H, dd, J 8.8, 5.2 Hz), 8.03 (1H, d, J 8.0 Hz), 7.99
(1H, d, J 8.4 Hz), 7.97 (1H, d, J 8.0 Hz) 7.71 (1H, dd, J 8.8, 2.0 Hz), 7.36 (2H, t,
J 8.8 Hz), 2.80 (3H, s), 2.68 (3H, s). Mp (DSC) 215 °C. LCMS (ESI+) 378 (MH+),
purity >98% (UV detection—averaged signal from 210 to 350 nm; 5-min
runtime; solvent system—from 3% organic (0.05% formic acid in MeCN)/97%
aqueous (0.05% formic acid in water) to 97% organic/3% aqueous, Waters
Atlantis column (dimensions 4.6 mm  50 mm, stationary phase particle size
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6, 442; (b) Westaway, S. M. J. Med. Chem. 2007, 50, 2589.
4. (a) Rami, H. K.; Thompson, M.; Stemp, G.; Fell, S.; Jerman, J. C.; Stevens, A. J.;
Smart, D.; Sargent, B.; Sanderson, D.; Randall, A. D.; Gunthorpe, M. J.; Davis, J. B.
Bioorg. Med. Chem. Lett. 2006, 16, 3287; (b) Gunthorpe, M. J.; Hannan, S. L.;
Smart, D.; Jerman, J. C.; Arpino, S.; Smith, G. D.; Brough, S.; Wright, J.; Egerton,
J.; Lappin, S. C.; Holland, V. A.; Winborn, K.; Thompson, M.; Rami, H. K.; Randall,
A.; Davis, J. B. J. Pharmacol. Exp. Ther. 2007, 321, 1183; (c) Doherty, E. M.; Fotsch,
C.; Bannon, A. W.; Bo, Y.; Chen, N.; Dominguez, C.; Falsey, J.; Gavva, N. R.; Katon,
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3
lm; flow-rate 3 mL/min).
16. Compound (32) was selective against a variety of ion channels, receptors and
enzymes through external (CEREP, 620% inhibition at 1
screening (pIC50/pKi <5.7).
lM) and in-house
17. Gunthorpe, M. J.; Smith, G. D.; Davis, J. B.; Randall, A. D. Pflugers Arch. 2001, 442,
668.