Design and synthesis of noncompetitive metabotropic glutamate receptor subtype 5 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.04.032

A series of diaryl amides was designed and synthesized as novel nonethynyl mGluR5 antagonists. The systematic variation of the pharmacophoric groups led to the identification of a lead compound that demonstrated micromolar affinity for the mGluR5. Further optimization resulted in compounds with improved binding affinities and antagonist profiles, in vitro.

Full text of DOI:10.1016/j.bmcl.2006.04.032

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3371–3375
Design and synthesis of noncompetitive metabotropic glutamate
receptor subtype 5 antagonists
Santosh S. Kulkarni,a Barbara Nightingale,b Christina M. Dersch,b
Richard B. Rothmanb and Amy Hauck Newmana,*
aMedicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, NIH, DHHS,
5500 Nathan Shock Drive, Baltimore, MD 21224, USA
bClinical Psychopharmacology Section, National Institute on Drug Abuse, Intramural Research Program, NIH, DHHS,
5500 Nathan Shock Drive, Baltimore, MD 21224, USA
Received 24 February 2006; revised 5 April 2006; accepted 6 April 2006
Available online 5 May 2006
Abstract—A series of diaryl amides was designed and synthesized as novel nonethynyl mGluR5 antagonists. The systematic vari-
ation of the pharmacophoric groups led to the identification of a lead compound that demonstrated micromolar affinity for the
mGluR5. Further optimization resulted in compounds with improved binding affinities and antagonist profiles, in vitro.
ꢀ 2006 Elsevier Ltd. All rights reserved.
L-Glutamate is a major excitatory neurotransmitter in
the central nervous system (CNS), which acts through
the ligand-gated ionotropic glutamate receptor or
through the G-protein coupled receptors (GPCR) called
metabotropic glutamate receptors (mGluR).1 The
mGluR5 belongs to the Group I subclass and is coupled
to the phosphoinositide/Ca2+ pathway, which mainly
mediates the excitatory effects of glutamate.1–3 Recently,
investigation into the role of mGluR5 in drug abuse has
led to speculation that this may be a new target for med-
ication development. For example, studies using either
an mGluR5 antagonist or mGluR5 knockout mice
showed reduced locomotor stimulant effects induced
by cocaine.4 Moreover, evidence that mGluR5 is
involved in the rewarding effects of morphine, nicotine,
and ethanol has also been reported.5 Thus, development
of selective mGluR5 antagonists may provide a novel
nondopaminergic strategy toward the discovery of drug
abuse medications. Additionally the mGluR5 has
recently been implicated in anxiety and depression thus
these antagonists might provide new therapeutic agents
toward the treatment of these CNS disorders.3
The first noncompetitive mGluR5 antagonists 1 and 2
were identified through a high throughput functional
assay, which subsequently led to the discovery of
compounds 3 and 4 (Fig. 1).6 These potent ethynyl-
based compounds have served as important tools to
investigate the role of mGluR5 in CNS pathophysiology
and drug abuse. However, cross target activity and in vi-
tro metabolism may limit further development of these
alkynes as medications.7 In order to further explore
SAR at mGluR5 and potentially avoid these confounds
to in vivo investigation, we report herein the design and
synthesis of a series of diaryl amides and their close
analogues, and results of in vitro binding and functional
evaluation at mGluR5.
OH
N
H3C
N
H3C
N
N
1
2
S
H3C
N
H3C
N
N
Keywords: Metabotropic glutamate receptor subtype 5; mGluR5;
Noncompetitive antagonists.
3
4
*
Figure 1. Noncompetitive antagonists of mGluR5: SIB-1757 1,
SIB-1893 2, MPEP 3, and MTEP 4.
Corresponding author. Tel.: +1 410 550 6568x114; e-mail:
anewman@intra.nida.nih.gov
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.032

3372
S. S. Kulkarni et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3371–3375
A molecular modeling study was initiated to visualize
potential ligand–receptor interactions. The X-ray crystal
structure of bovine rhodopsin was used as a template for
the homology modeling of the transmembrane region of
the mGluR5.8,9 Based on site-directed mutagenesis data
and the binding affinities of MPEP (3), the ligand bind-
ing site was predicted (Fig. 2).10 The binding site consists
of two hydrophobic regions, wherein the aromatic rings
interact, with a linker in between, to position these
groups in proper orientation. Thus, a simple ligand de-
sign strategy was employed to first explore the SAR
around these binding sites by varying rings ‘a’ and ‘b’
(Fig. 2). In the course of our studies, others have report-
ed novel mGluR5 antagonists that have replaced the al-
kyne linker with additional functional groups and
heterocyclic rings.11 In this study, we focused on the
amide linkage, to determine if (1) it could mimic the bio-
logical activity of the alkyne and (2) for ease of synthesis
that allowed the preparation of a larger set of com-
pounds to develop SAR.
or Heck coupling reactions, respectively, to obtain com-
pounds 13a and 13b; similarly compound 10s was
hydrogenated in the presence of 10% Pd/C. The deben-
zylated compound was then treated with 2-bro-
mophenylethylbromide to give compound 13c.
The piperidine-substituted compounds 17 were synthe-
sized by Fmoc protection of the DL-pipecolic acid
followed by amide synthesis under a modified Schotten–
Baumann condition and deprotection of the Fmoc group
by treatment with 4-aminomethyl piperidine. The depro-
tected amide 16 was then reacted with various arylalkyl
bromides to obtain compounds 17 (Scheme 3).12
These compounds were evaluated for binding affinity at
mGluR5 in a rat brain membrane preparation using
[3H]MPEP as the radioligand.13 Most structural varia-
tions were not well tolerated as many compounds in
the initial series were inactive, at a concentration of
100 lM (data not shown). Representative structures
and binding data are shown in Table 1 and compared
to reference compounds 1 and 2. In general, the com-
pounds with variation in the linker between the aromat-
ic rings ‘a’ and ‘b’ (Fig. 2) were inactive (e.g., 6a, 11a,
and 12a in Table 1).
A series of compounds was synthesized as shown in
Schemes 1–3, wherein 6-methyl picolinaldehyde 5 was
refluxed with aniline and then reduced with LAH
(Scheme 1) to provide compound 6.
Benzamide analogues of type 9 and 10 were synthesized
by reacting respective acid chlorides with 2-amino-4-
methyl thiazole 7 and 2-amino 6-methyl pyridine 8,
respectively (Scheme 2). The appropriately substituted
benzamide 10, like 10a, was either reduced with LAH
to give compound 11a or, for example, compound 10p
and 10n were subjected to palladium-catalyzed Suzuki
Substitution with the amide bond linker however pro-
vided some compounds (9a and 10a) that showed mod-
erate affinity at mGluR5 with a slope nearing unity
suggesting competitive displacement of the radioligand.
There was a considerable loss in affinity when the 6-
methyl group in ring ‘a’ (10b) was eliminated. Compar-
ison of activities for compounds 2-naphthyl (10d), which
was inactive and 1-naphthyl (10c), which is moderately
active, suggested that there is limited steric tolerance in
this region. Substitution at the 30 position of the aromat-
ic ring ‘b’ improved the binding affinity substantially
(e.g., 10f IC50 = 1.73 lM), however substitution at 20
(10e) and 40 (10g) positions completely lost activity. A
comparable activity of compound 10f to parent com-
pounds 1 and 2 provided strong support to further
explore the SAR around this new lead compound.
From these initial data a focused set of compounds with
30-substitution in the ring ‘b’ with the amide linker was
synthesized, and representative structures and binding
data are shown in Table 2. In addition, the active com-
pounds from this set were evaluated in a functional
assay measuring the inhibition of agonist-induced
phosphoinositide hydrolysis at mGluR5 in CHO cells
and are compared to reference compounds 3 and
4.14,15 Replacement of the pyridyl ‘a’ ring with thiazole,
analogous to MTEP (4), was well tolerated as com-
pound 9d was as active as compound 10i. Replacing
the 6-methyl group in ring ‘a,’ which could be a meta-
bolic liability, with a Cl atom (10q) maintained the
affinity. Substitution with the electronegative CN
(10o), Br (10p) or I (10n) at the 30 position in ring
‘b’ yielded the most active compounds (IC50 = 0.33–
1.08 lM) in this series with moderate potency as
antagonists in the functional assay (IC50 = 5–11 lM).
However, substitution with bulky CF3 (10k), SO2CH3
(10l) or OSO2CH3 (10m) reduced the binding affinity
HN
O
a
HN
H3C
N
R
O O
S
b
HN
Figure 2. Homology model of mGluR5 for ligand design.
(a), (b)
H
H
N
H3C
N
H3C
N
O
5
6
Scheme 1. Synthesis of compound 6. Reagents and conditions: (a)
aniline, methanol, reflux 24 h; (b) LAH, THF, 0 ꢁC 30 min.

S. S. Kulkarni et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3371–3375
3373
S
O
R2
S
R1
R3
R4
R1
Or
R2
N
NH2
NH2
N
N
H
R3
R4
7
R1
N
N
9
(a)
(b)
Or
H
O
R2
11
R1
N
R3
R4
R1
N
N
H
8
10
(c)
(d)
O
O
O
R3
S
R1
N
N
R1
N
N
H
H
CH3
12
13
Scheme 2. Synthesis of compounds 9–13. Reagents and conditions: (a) acid chloride, pyridine, rt, 1 h; (b) LAH, THF, reflux 2 h; (c) p-TsCl, toluene,
1,4-dioxane, reflux 4 h; (d) phenyl boronic acid, Pd(PPh3)4, 2 M aq Na2CO3, toluene, ethanol, reflux 2 h, 13a; styrene, Pd(OAc)2, o-tolyl phosphine,
TEA, acetonitrile, 100 ꢁC, 20 h, 13b; 10% Pd/C, H2, MeOH; 2-phenylethylbromide, anhyd K2CO3, DMF, 50 ꢁC, 24 h, 13c.
O
O
O
Fmoc
(a)
(b), (c), (d)
HO
NH
HO
N
H3C
N
N
H
NH
14
15
16
(e)
O
R1
H3C
N
N
N
H
17
Scheme 3. Synthesis of compound 17. Reagents and conditions: (a) Fmoc-Cl, 10% w/v Na2CO3, 1,4-dioxane, rt, 2 h; (b) SOCl2, DCM, cat. DMF, rt,
3 h; (c) 2-amino-6-methyl pyridine, aq NaHCO3, CHCl3, rt, 1 h; (d) 4-aminomethyl piperidine, CHCl3, rt, 12 h; (e) 37% HCHO, HCOOH, reflux, 3 h
17a; arylalkyl bromides, anhyd K2CO3, DMF, 80 ꢁC, 2 h, 17b,c; p-TsCl, TEA, DCM, 0–5 ꢁC, 1 h, 17d.
Table 1. Representative structures and in vitro activities of compounds
R2
R2
S
R1
R3
R4
Y
R3
R4
Y
R1
N
X
N
X
9
6, 10-12
Compound
R1
X
Y
R2
R3
R4
Binding affinity IC50 (lM)
6a
CH3
CH3
CH3
CH3
CH3
H
CH2
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
—
NH
H
H
H
H
H
H
H
H
H
H
H
H
H
NAa
NA
11a
12a
9a
CH2
SO2
CO
CO
CO
CO
CO
CO
CO
CO
—
H
CH3
H
NA
65.04 2.87
35.00 1.00
95.39 6.26
62.76 1.74
NA
10a
10b
10c
10d
10e
10f
10g
1
H
H
CH3
CH3
CH3
CH3
CH3
—
1-Naphthylb
H
H
2-Naphthylc
Cl
H
H
H
NA
1.73 0.10d
NA
Cl
H
H
H
Cl
—
—
—
—
—
—
1.17 0.07
1.08 0.06
2
—
—
—
a Inactive at 100 lM.
b Ring ‘b’ (Fig. 2) is 1-naphthyl.
c Ring ‘b’ (Fig. 2) is 2-naphthyl.
d In functional assay 66% inhibition at 10 lM.
at mGluR5. Additionally substitution with large hydro-
phobic groups (styryl 13b, O-benzyl, 10s, etc.) substan-
tially reduced binding affinity.
To further explore the importance of aromaticity in ring
‘b’ and to potentially access an additional binding
domain for added interactions, which might improve

3374
S. S. Kulkarni et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3371–3375
Table 2. Representative structures and in vitro activities of com-
pounds with 30-substitution in the ‘b’ ring
amide analogues generally showed a ꢀ10-fold loss in
functional potency as antagonists, as compared to their
binding affinities at mGluR5, which has not been de-
scribed for the ethynyl analogues reported to date.15,16
Although this may simply be due to a difference in con-
ditions between these two in vitro assays, the possibility
exists that changes in conformation, at the receptor pro-
tein level, may be affecting these differences. The novel
series of compounds described in this communication
provide structurally distinct probes to investigate the
role of mGluR5 in CNS disorders. The SAR developed
herein has lead to the design of a new set of potential
mGluR5 antagonists for in vivo investigation that will
be reported in due course.
S
O
O
R1
R3
R3
R1
N
N
N
N
H
H
10, 13
9
Compound R1 R3
IC50 (lM)
Functional
Binding
affinity
activity
NTc
9b
9c
CH3 3-Pyridyla
CH3 Cl
NAb
5.49 0.23 15.00 7.00
9.10 0.39 NT
9d
CH3 OCH3
CH3 3-Pyridyla
CH3 OCH3
CH3 CH3
10h
10i
10j
10k
10l
10m
10n
10o
10p
10qd
10r
10s
13a
13b
13c
3
NA
NT
9.76 0.43 46.00 18.00
1.84 0.14
18.68 1.11 NT
NA NT
5.90 1.10
CH3 CF3
CH3 SO2CH3
CH3 OSO2CH3
Acknowledgments
83.57 3.90 NT
1.08 0.07 10. 80 3.30
CH3
I
S.S.K. was supported by a NIH-visiting fellowship, B.N.
was supported by a post-baccalaureate IRTA fellow-
ship. Functional assay data were provided by the
National Institute on Mental Health-Psychoactive Drug
Screening Program (PDSP) with special thanks to Drs.
Linda Brady and Bryan Roth for their support. Also,
the authors wish to acknowledge Dr. Jarda Wroblewski
for his contributions through the PDSP contract and
thoughtful discussion of the functional assay results.
This work is supported by the NIDA-IRP, NIH.
CH3 CN
CH3 Br
Cl Cl
0.33 0.02
0.65 0.02
5.33 1.20
5.48 0.73
1.53 0.06 12.70 1.69
56.97 3.26 NT
33.04 1.66 NT
CH3 OPh
CH3 OCH2Ph
CH3 Ph
7.30 0.39 18.30 1.52
CH3 trans-CH@CHPh NA
CH3 O(CH2)2Ph
NT
23.55 1.37 NA
—
—
—
—
0.013 0.001 0.039 0.00815
4
NT
0.462 0.11215
a Ring ‘b’ (Fig. 2) is 3-pyridyl.
b Inactive at 100 lM.
c Not tested.
Supplementary data
d Synthesized from 6-chloro-2-aminopyridine.
Supplementary data associated with this article can be
found in the online version at doi:10.1016/j.bmcl.2006.
04.032.
binding affinity, saturated 3-piperidinyl amides were
synthesized. However, these compounds were inactive,
thus suggesting a very limited tolerance in this binding
region of the receptor (Table 3).
References and notes
In summary, a putative ligand-binding site at the trans-
membrane domain region based on the bovine rhodop-
sin crystal structure aided in the design of a novel series
of potential mGluR5 antagonists. The SAR in this series
of diarylamides generally corresponded to those report-
ed for the ethynyl and pyridyl amide analogues16 but
unlike most earlier reports, several amide-linked com-
pounds in the present series showed moderate activity
as mGluR5 antagonists. Of note, we observed that these
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Table 3. Representative structures and in vitro activities of piperidine
3-carboxamides
O
R1
H3C
N
N
H
N
17
Compound
R1
CH3
CH2Ph
Binding affinitya
17a
17b
17c
17d
NAb
14
CH2-m-ClPh
SO2-p-Tol
31
31
a Percentage inhibition at 100 lM.
b Not active.

S. S. Kulkarni et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3371–3375
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data for all other compounds are reported in Supporting
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9. A putative binding site is depicted in Figure 2, the details
of the homology modeling will be published elsewhere.
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13. Rat membranes were prepared each day using a partially
thawed frozen rat brain which was homogenized using a
Brinkman Polytron (setting 6 for 10 s) in 10 mL/brain of
ice-cold 10 mM Tris–HCl, pH 7.0. Membranes were then
centrifuged twice for 10 min each at 30,000g. After the
second centrifugation, the membranes were suspended in
240 mL/brain of ice-cold 50 mM Tris–HCl, pH 7.0,
containing 1% bovine serum albumin. The mGluR5
binding sites were labeled using [3H]MPEP (1 nM). The
[3H]MPEP was in a protease inhibitor cocktail consisting
of 4 lg/mL leupeptin, 2 lg/mL chymostatin, and 10 lg/
mL bestatin. The binding assays were carried out in
12 · 75 mm polystyrene tubes that were pre-filled with
50 lL of drug, 100 lL of 100 mM NaCl, and 100 lL of
radioligand. The drugs were made up in ice-cold 50 mM
Tris–HCl, pH 7.0, with 1% BSA. The radioligand was
displaced by 10 concentrations of test drug three times.
The experiment was initiated with the addition of 750 lL
of the prepared membranes. Samples were incubated in a
final volume of 1 mL, for 2.5 h (steady-state) at 4 ꢁC. After
incubation, the samples were filtered with a Brandel cell
harvester over Whatman GF/B filters presoaked in wash
buffer (ice-cold 10 mM Tris–HCl, pH 7.0) containing 0.5%
poly(ethylenimine). The nonspecific binding was deter-
mined using 10 lM MPEP. Typical total and nonspecific
cpms observed for the binding assays were 4000 and 800,
respectively. The IC50 and slope factor (N) were obtained
by using the program MLAB.
14. Shi, Q.; Savage, J. E.; Hufeisen, S. J.; Rauser, L.;
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12. All compounds were purified by flash chromatography
and characterized by spectroscopic and microanalytical
techniques. The final products were crystallized as the
HBr salts for biological evaluation. The spectral data
supported the assigned structures, for example, N-(6-
methylpyridin-2-yl)biphenyl-3-carboxamide
hydrobro-
mide 13a, mp 218–220 ꢁC; 1H NMR (400 MHz, CDCl3)
d 2.47 (s, 3H), 6.93–9.95 (d, J = 7.6 Hz, 1H), 7.37–7.41
(m, 1H), 7.45–7.49 (m, 2H), 7.54–7.58 (t, J = 7.6 Hz,
1H), 7.61–7.63 (m, 2H), 7.63–7.67 (t, J = 7.6 Hz, 1H),
7.76–7.79 (m, 1H), 7.87–7.90 (dt, J = 7.6, 1.2 Hz, 1H),
8.13–8.14 (t, J = 2.0 Hz, 1H), 8.20–8.22 (d, J = 8.4 Hz,
1H), 8.62 (br s, 1H); 13C NMR (101 MHz, CDCl3) d
24.46, 111.20, 119.72, 126.06, 126.22, 127.41, 128.07,
129.12, 129.42, 131.02, 135.12, 138.93, 140.15, 142.14,
150.92, 157.07, 165.67; IR (neat, cmꢁ1) 3283.80, 3059.10,
1676.40, 1577.80; GC–MS (EI) m/z 288 (M+); Anal.
(C19H16N2OÆHBr) C, H, N. The spectral and analytical