Heterobiaryl and heterobiaryl ether derived M5 positive allosteric modulators

Article abstract of DOI:10.1016/j.bmcl.2010.08.042

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M₅-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G_q mAChR M₁, M₃, M₅ PAM. An iterative parallel synthesis approach was employed to incorporate basic heterocycles to improve physiochemical properties.

Full text of DOI:10.1016/j.bmcl.2010.08.042

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5617–5622
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Heterobiaryl and heterobiaryl ether derived M5 positive allosteric modulators
Thomas M. Bridges a,d, J. Phillip Kennedy b, Corey R. Hopkins a,c,d, P. Jeffrey Conn a,c,d, Craig W. Lindsley a,b,c,d,
⇑
a Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
c Vanderbilt Program in Drug Discovery, Nashville, TN 37232, USA
d Vanderbilt Specialized Chemistry Center (MLPCN), Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-prefer-
ring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq
mAChR M1, M3, M5 PAM. An iterative parallel synthesis approach was employed to incorporate basic
heterocycles to improve physiochemical properties.
Received 20 July 2010
Revised 5 August 2010
Accepted 9 August 2010
Available online 12 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
M5
mAChR
PAM
Allosteric
In the course of our program to develop allosteric ligands for
GPCRs,1–6 we recently described the identification of VU0119498
(1), a pan Gq muscarinic acetylcholine receptor (mAChR) M1, M3,
M5 positive allosteric modulator (PAM).7 Application of an iterative
parallel synthesis approach identified key structural elements with-
in the VU0119498 scaffold that eliminated M3 and M5 activity
parallel synthesis approach.11 For the first round of parallel synthe-
sis, we first held the biphenyl moiety constant and surveyed a
diverse range of substituents (lipophilic, polar, basic, and acidic
functionalities) in the 5-position as possible replacements for the
5-OCF3 moiety. Libraries were prepared according to Scheme 1,
wherein 5-methoxyisatin 6 is alkylated with 4-bromobenzyl bro-
mide to provide 7 in 65% yield, followed by a microwave-assisted
Suzuki coupling to install the biaryl motif affording 8 in 82% yield.
A subsequent BBr3-mediated demethylation delivered the key sub-
strate 9 for library production in 83% yield. Depending on the elec-
trophile, a number of alkylation/SNAr/Mitsunobu conditions were
employed to deliver the final 44 library members 10.12 The library
affording VU0366369 (2),
a highly selective M1 PAM (M1
EC50 = 0.83 M, >30
l
l
M vs M2–M5).8 Further SAR discovered a criti-
cal 5-OCF3 moiety on the isatin core that engendered selective M5
activity that led to the development of the first M5 PAM,
VU0238429 (3).9 Optimization of VU0238429, again employing iter-
ative parallel synthesis, led to the development of VU0365114 (4)
and VU0400265 (5) with excellent selectivity for the M5 subtype
was then triaged by a single point (10 lM) screen for their ability
(Fig. 1).10 While 4 (M5 EC50 = 2.7
EC50 = 1.9 M, >30
l
M, >30
l
M vs M1–M4) and 5 (M5
to potentiate an EC20 of ACh in M5-CHO cells (Fig. 3). Surprisingly,
not a single library member 10 was able to significantly potentiate
the EC20 of ACh in M5-CHO cells; however, three analogs 10ee,
10gg, and 10kk, all containing a basic amine, did decrease the
ACh EC20, suggesting that they may be putative antagonists or
NAMs. Thus, the 5-OCF3 was essential for M5 PAM activity and
would be retained in future libraries.
In parallel with the library work, we prepared a number of single-
ton analogs (Fig. 4) following the synthetic routes outlined in
Scheme 1. In the related M1 PAM series, we found that strategic
introduction of fluorine atoms maintained M1 selectivity while
increasing potency.8,13 In the present case, as with 11 and 12, this
strategy did not translate well into the M5 PAM series, leading to a
loss in both potency and efficacy. In our M4 PAM series, a piperonyl
moiety was equipotent to a 4-OMe group (as in 3); this modification
was also productive here, providing 13, a highly efficacious M5 PAM
l
lM vs M1–M4) marked notable advances for
the study of M5 function with small molecule tools, both are lipo-
philic compounds (log Ps >4.5) with limited solubility and overall
poor physiochemical properties.8–10 This Letter, describes efforts
to identify alternatives for both the 5-OCF3 moiety, and heterocyclic
replacements for the phenyl rings that would retain M5 potency and
subtype selectivity while providing basic nitrogen atoms from
which salts could be formed to improve solubility and physiochem-
ical properties.
Our optimization strategy is outlined in Figure 2, and as SAR
with allosteric ligands is often shallow, we employed an iterative
⇑
Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 343 6532.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.042

5618
T. M. Bridges et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5617–5622
O
O
O
F3CO
O
O
O
N
N
N
N
Br
OMe
F
NMe
1
2
VU0238429 (3)
VU0119498 ( )
VU0366369 ( )
M1 EC50 ~30%@30 µM
M2 EC50 > 30 µM
M1 EC50 = 6.1 µM
M2 EC50 > 30 µM
M3 EC50 = 6.4 µM
M1 EC50 = 0.83 µM
M2 EC50 > 30 µM
M
M
3 EC50 ~30%@30 µM
M
3 EC50 > 30 µM
µM
4 EC50 > 30
M5 EC50 = 1.1 µM
µM
M4 EC50 > 30
M4 EC50 > 30 µM
M5 EC50 > 30 µM
M5 EC50 = 4.6 µM
O
O
F3CO
F3CO
O
O
N
N
O
4
5
VU0365114 ( )
VU0400265 ( )
M
1 EC50 > 30 µM
M2 EC50 > 30 µM
M3 EC50 > 30 µM
M4 EC50 > 30 µM
M1 EC50 > 30 µM
M2 EC50 > 30 µM
M3 EC50 > 30 µM
M4 EC50 > 30 µM
M
5 EC50 = 2.7 µM
M5 EC50 = 1.9 µM
Figure 1. HTS lead VU0119498, a pan Gq mAChR M1, M3, M5 PAM which was optimized to provide both an M1 selective PAM, VU0366369, and an M5-preferring PAM,
VU0238429. Further optimization of VU0238429 led to the development of two highly selective M5 PAMs, VU0365114 and VU0400265. Data represent means from at least
three independent determinations with similar results using mobilization of intracellular calcium in M1–M5 CHO cells (M2 and M4 cells co-transfected with Gqi5).
activity comparable to 4 (M5 EC50s 1.6–2.8 lM), but with low
efficacy (M5 ACh Max <60%).
Convert to tertiary hydroxyl
F3CO
We then replaced the benzylic phenyl ring with either a 2- or
3-pyridyl ring and explored aryl and heteroaryl rings in the 4-posi-
tion (Scheme 3). Thus, 5-trifluoromethoxyisatin 16 was alkylated
with either 5-bromo-2-(bromomethyl)pyridine or 5-(bromo-
methyl)2-chloropyridine to provide 19 and 20, respectively, in
98% isolated yields. Suzuki couplings with heterocyclic boronic
acids delivered libraries of analogs 21 and 22.
O
Regioisomeric pyridines
O
N
Replacements for OCF3
As shown in Table 1, this effort produced several active analogs
with a balance of M5 potency and efficacy. Notably, the 3-pyridyl
analogs 22 and the chloro intermediate in this series 20 proved
to be uniformly active, affording M5 PAMs with modest potency
Polar moieties
Figure 2. Optimization strategy for VU0365114 (4), a highly selective M5 PAM.
(M5 EC50s 2.4–4.4 lM and 50–80% M5 ACh Max). Interestingly,
heterobiaryl analogs 21b and 21c were devoid of M5 PAM activity,
while the phenyl congener 21a was of comparable potency to 4,
but with diminished efficacy (47% M5 ACh Max). Gratifyingly, HCl
salts could be generated for analogs 21 and 22 with improved sol-
ubility across vehicles as compared to 4. Moreover log P was re-
of comparable potency to 4. Finally, we surveyed installation of the
biphenyl and phenyl ether moieties in the 3-position versus the 4-
position, 14 and 15, respectively, but all M5 PAM activity was lost
(M5 EC50 >30 lM). In addition, replacement of the isatin ketone car-
duced by an order of magnitude (log P = 4.6 for
log P = 3.6 for 22a and log P = 3.0 for 22b).
4 whereas
bonyl with either a tertiary alcohol or a spirocyclopropane resulted
in analogs devoid of M5 PAM activity. These data influenced the de-
sign of subsequent heterocyclic-containing libraries.
Finally, we prepared a small library based on biaryl ether 5,
replacing the distal phenyl ring with various heterocycles. Chemis-
try to access these analogs proved arduous under Ullmann cou-
pling conditions. Therefore, our synthetic route (Scheme 4)
employed methyl 4-hydroxybenzoate 23 for SNAr reactions with
heteroaryl chlorides to produce analogs 24. Reduction with DIBAL
delivered benzylic alcohols 25 which were then converted to the
corresponding bromides 26 and employed in alkylation chemistry
with 16 to deliver analogs 27.
Based on the preceding data, the next library was designed
wherein the 5-OCF3 was held constant, the benzylic ring was
retained as phenyl and the 4-position of the benzylic phenyl ring
was substituted with various heterocycles (Scheme 2). 5-Trifluoro-
methoxyisatin 16 was alkylated with 4-bromobenzyl bromide to
provide 17 in 99% isolated yield. Suzuki couplings with heterocyclic
boronic acids delivered analogs 18 in low yields ranging between 9%
and 18%. From this effort (Fig. 5), three analogs displayed M5 PAM

T. M. Bridges et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5617–5622
5619
O
O
O
O
O
O
b
a
O
O
O
N
N
N
H
Br
6
7
8
O
O
O
HO
d or e or f
R
c
O
O
N
N
9
10
Scheme 1. Reagents and conditions: (a) 4-bromobenzyl bromide, K2CO3, KI, DMF, rt, 48 h (65%); (b) PhB(OH)2, 5 mol % Pd(PPh3)4, 1.0 M aq Cs2CO3, THF, mw, 120 °C, 20 min
(82%); (c) BBr3, DCM, 0 °C to rt, 2 h (83%); (d) R-X, Cs2CO3, KI, DMF, mw, 120 °C, 30 min (avg. 20% for 31 analogs 10); (e) ROH, PS-PPh3, DIAD, THF, rt (avg. 4% for 10 analogs 10);
(f) Het-X, Cs2CO3, DMF, 160 °C, 20 min (avg. 10%, three analogs 10).
Four analogs 27a–27d displayed M5 PAM activity (Fig. 6). The
phenyl moiety of could be replaced with 2-pyridyl (27a,
M5 EC50 = 3.2 M, 46% ACh Max), 6-fluoro-2-pyridyl (27b, M5
EC50 = 1.5 M, 62% ACh Max), 6-methoxy-2-pyridyl (27c,
M5 EC50 = 2.2 M, 51% ACh Max), or a 2-thiazolyl (27d, M5
EC50 = 2.8 M, 58% ACh Max). Again, HCl salts could be generated
assays at a standard 30 lM concentration, 22a elicited a robust
5
14-fold leftward shift and 27b displayed a sixfold leftward shift
of the ACh concentration response curves (Fig. 7). Compound 22a
was found to possess ꢀ20% allosteric agonism. Notably, the fold-
shifts were equivalent to those of the phenyl analogs 4 (10-fold
shift) and 5 (fivefold shift). We then evaluated selectivity of these
l
l
a
l
l
for analogs 27 with improved solubility across vehicles as compared
to 5. Moreover log P was reduced by an order of magnitude.
From this effort, two analogs emerged 22a (VU0415478), a
heterobiaryl derivative, and 27b (VU0414747), a heterobiaryl ether
congener, worthy of further evaluation. In acetylcholine fold-shift
heterocyclic analogs versus the other mAChRs. Using a 30 lM, fold-
shift selectivity assay protocol,2–7 neither 22a nor 27b showed any
significant effect on M1–M4; thus, 22a and 27b are highly selective
M5 PAMs. Moreover, the diminished lipophilicity translated
directly into a cleaner ancillary pharmacology profile. For example,
Figure 3. ACh EC20 triage screen of 44 analogs 10a–10rr at 10 lM in M5-CHO cells by intracellular calcium mobilization assay. Data represent means from at least three
independent determinations with similar results.

5620
T. M. Bridges et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5617–5622
O
O
O
F3CO
F3CO
F3CO
O
O
O
F
N
N
N
O
F
F
O
VU0366625 (11)
VU0366626 (12)
M5 EC50 >30 µM
VU0366628 (13)
M5 EC50 = 5.9 µM
63% ACh Max
M5 EC50 = 3.2 µM
90% ACh Max
O
O
F3CO
F3CO
O
O
N
N
O
)
15
VU0403894 (
VU0403893 (14)
M5 EC50 >30 µM
M5 EC50 >30 µM
Figure 4. Singleton analogs designed to test key design elements to influence heterocyclic library design.
O
O
F3CO
F3CO
O
F3CO
b
a
O
O
O
N
N
N
H
Het
Br
16
17
18
Scheme 2. Reagents and conditions: (a) 4-bromobenzyl bromide, K2CO3, KI, DMF, rt, 48 h (99%); (b) Het-B(OH)2, 5 mol % Pd(PPh3)4, 1.0 M aq Cs2CO3, THF, mw, 120 °C, 20 min
(9–18%).
O
O
O
F3CO
F3CO
F3CO
O
O
O
N
N
N
N
N
N
N
VU0415483 (18a)
VU0415484 (18b)
VU0415485 (18c)
M5 EC50 = 1.6 µM
51% ACh Max
M5 EC50 = 2.8 µM
60% ACh Max
M5 EC50 = 2.1 µM
53% ACh Max
Figure 5. M5 PAM analogs 18a–18c with heterocycles in the 4-position of the biaryl motif.
O
O
F3CO
O
F3CO
F3CO
b
a
O
O
N
O
N
X
X
Y
Y
N
H
R
Z
16
19 X = N, Y = CH, Z = Br
20
21
22
X = N, Y = CH
X = CH, Y = N
X = CH, Y = N, Z = Cl
Scheme 3. Reagents and conditions: (a) 5-bromo-2-(bromomethyl) pyridine or 5-(bromomethyl)2-chloropyridine, K2CO3, KI, DMF, rt, 48 h (98%); (b) (Ph)Het-B(OH)2, 5 mol %
Pd(PPh3)4, 1.0 M aq Cs2CO3, THF, mw, 120 °C, 20 min (5-11%).

T. M. Bridges et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5617–5622
5621
Table 1
Structures and activities of analogs 21 and 22
O
O
F3CO
F3CO
O
O
N
N
N
N
R
R
21
22
Compd
R
M5 Ec50
(l
M)a
M5 %ACh Maxa
20
21a
21b
21c
22a
22b
22c
Cl
Ph
2.4
3.1
>30
>30
3.8
80
47
ND
ND
76
53
50
3-Pyridyl
4-Pyridyl
Ph
3-Pyridyl
4-Pyridyl
Figure 7. Human M5 ACh fold-shift assay at a standard 30
heterocyclic analogs 22a (VU0415478),
(VU0414747), a heterobiaryl ether congener.
l
M concentration for
a
heterobiaryl derivative, and 27b
4.0
4.4
a
Average of at least three independent determinations.
limited its utility as a tool compound to study selective M5 activa-
tion. In the same assay panel, 27b was found to possess modest
activities for 11 of the 68 targets, and only significant activity at
NET and H1.
O
O
a
b
OMe
OMe
OH
RO
In summary, an iterative parallel synthesis approach rapidly
identified key heterocyclic replacements for phenyl moieties in
two related biaryl and biaryl ether M5 PAM scaffolds. SAR was
steep, but key analogs 22a and 27b maintained M5 PAM activity,
robust leftward shifts of the ACh CRC and mAChR subtype selectiv-
ity. In addition, HCl salts could be formed and log P was reduced by
an order of magnitude. Further in vitro pharmacology and electro-
physiology studies with 22a and 27b are in progress and will be re-
ported in due course.
HO
RO
23
24
25
O
F
O
c
d
Br
F
O
F
N
RO
R
O
26
27
Acknowledgments
Scheme 4. Reagents and conditions: (a) Cs2CO3, DMF, 130 °C, 5–12 h (57–91%); (b)
1 M DIBAL, toluene, 0 °C to rt, 2 h (86–94%); (c) PBr3, CH2Cl2, 0 °C (19–53%); (d) 16,
K2CO3, KI, DMF, mw, 120 °C, 30 min (5–32%).
The authors thank NIMH (1RO1 MH082867) and the MLPCN
(1U54 MH084659) for support of our program in the development
of subtype selective allosteric ligands of mAChRs. Vanderbilt is a
Specialized Chemistry Center within the MLPCN.
5 showed significant activity (>50% inhibition at 10 lM) for 32 tar-
gets in a panel14 of 68 GPCRs, ion channels, and transporters which
O
O
F
F
O
F
F
O
F
O
O
F
F
N
N
N
N
O
O
27a
27b
(VU0414747)
(VU0414746)
M5 EC50 = 3.2 µM
46% ACh Max
M
5 EC50 = 1.5 µM
62% ACh Max
O
O
F
F
O
F
F
O
OMe
O
N
O
N
F
F
N
N
S
O
O
27c
27d
(VU0414749)
(VU0414748)
M
5 EC50 = 2.2 µM
51% ACh Max
M
5 EC50 = 2.8µM
58% ACh Max
Figure 6. M5 PAM heterobiaryl ether analogs 27a–27d.

5622
T. M. Bridges et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5617–5622
7. Marlo, J. E.; Niswender, C. M.; Days, E. L.; Bridges, T. M.; Xiang, Y.; Rodriguez, A.
References and notes
L.; Shirey, J. K.; Brady, A. E.; Nalywajko, T.; Luo, Q.; Austin, C. A.; Williams, M. B.;
Kim, K.; Williams, R.; Orton, D.; Brown, H. A.; Lindsley, C. W.; Weaver, C. D.;
Conn, P. J. Mol. Pharmacol. 2009, 75, 577.
1. (a) Conn, P. J.; Jones, C.; Lindsley, C. W. Trends Pharmacol. Sci. 2009, 30, 148; (b)
Conn, P. J.; Lindsley, C. W.; Jones, C. Trends Pharmacol. Sci. 2009, 30, 25; (c) Conn,
P. J.; Christopoulos, A.; Lindsley, C. W. Nat. Rev. Drug Discov. 2009, 8, 41; (d)
Lindsley, C. W.; Niswender, C. M.; Engers, D. W.; Hopkins, C. R. Curr. Top. Med.
Chem. 2009, 9, 949.
8. Bridges, T. M.; Kennedy, J. P.; Noetzel, M. J.; Breininger, M. L.; Gentry, P. R.; Cho,
H. P.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2010, 20, 1972.
9. Bridges, T. M.; Marlo, J. E.; Niswender, C. M.; Jones, J. K.; Jadhav, S. B.; Gentry, P.
R.; Plumley, H. C.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W. J. Med. Chem. 2009,
52, 3445.
10. Bridges, T. M.; Kennedy, J. P.; Cho, H. P.; Breininger, M. L.; Gentry, P. R.;
Hopkins, C. R.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2010, 20, 558.
11. Kennedy, J. P.; Williams, L.; Bridges, T. M.; Daniels, R. N.; Weaver, D.; Lindsley,
C. W. J. Comb. Chem. 2008, 10, 345.
12. Library members 10, R=: a, trifluopropyl; b, carboxymethyl; c, methyl; d,
cyclobutylmethyl; e, n-propyl; f, n-butyl; g, cyclohexylmethyl; h, benzyl; i, 4-
OMeBn; j, 3-OMeBn; k, 2-FBn; l, 4-FBn; m, 2,6-diFBn; n, 2-ClBn; o, 2-CF3Bn; p,
4-CF3Bn; q, 2,4-diFBn; r, 4-OCF3Bn; s, 2-MeBn; t, 4-ClBn; u, 3-ClBn; v, 3-CF3Bn;
w, 2-CF3Bn; x, 3-OCF3Bn; y, 2,5-diFBn; z, i-Bu; aa, Et; bb, 3-FBn; cc, 3-CF3-4-
OMeBn; dd, morpholinoethyl; ee, 3-methyl-1-methylpiperidine; ff, 2-OMeBn;
gg, N,N-dimethylethyl; hh, 4-pyridylmethyl; ii, 3-pyridylmethyl; jj, 2-
pyridylmethyl; kk, pyrrolidinyl ethyl; ll, 2-F phenethyl; mm, 2-CF3
phenethyl; nn, 2-Cl phenethyl; oo, 2-Me phenethyl; pp, trifluoroethyl; qq, 2-
pyridyl; rr, 2-pyrimidyl.
13. Yang, F. V.; Shipe, W. D.; Bunda, J. L.; Nolt, M. B.; Wisnoski, D. D.; Zhao, Z.;
Barrow, J. C.; Ray, W. J.; Ma, L.; Wittman, M.; Seager, M.; Koeplinger, K.;
Hartman, G. D.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2010, 20, 531.
14. For information on the ancillary pharmacology panel see the Lead Profiling
Screen at www.ricerca.com.
2. (a) Brady, A.; Jones, C. K.; Bridges, T. M.; Kennedy, P. J.; Thompson, A. D.;
Heiman, J. U.; Breininger, M. L.; Gentry, P. R.; Yin, H.; Jadhav, S. B.; Shirey, J.;
Conn, P. J.; Lindsley, C. W. J. Pharmacol. Exp. Ther. 2008, 327, 941; (b) Kennedy, J.
P.; Bridges, T. M.; Gentry, P. R.; Brogan, J. T.; Kane, A. S.; Jones, C. K.; Brady, A. E.;
Shirey, J. K.; Conn, P. J.; Lindsley, C. W. ChemMedChem 2009, 4, 1600.
3. (a) Jones, C. K.; Brady, A. E.; Davis, A. A.; Xiang, Z.; Bubser, M.; Tantawy, M. N.;
Kane, A.; Bridges, T. M.; Kennedy, J. P.; Bradley, S. R.; Peterson, T.; Ansari, M.;
Baldwin, R. M.; Kessler, R.; Deutch, A.; Lah, J. L.; Levey, A. I.; Lindsley, C. W.;
Conn, P. J. J. Neurosci. 2008, 28, 10422; (b) Bridges, T. M.; Brady, A. E.; Kennedy,
J. P.; Daniels, N. R.; Miller, N. R.; Kim, K.; Breininger, M. L.; Gentry, P. R.; Brogan,
J. T.; Jones, J. K.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2008, 18,
5439; (c) Miller, N. R.; Daniels, N. R.; Bridges, T. M.; Brady, A. E.; Conn, P. J.;
Lindsley, C. W. Bioorg. Med. Chem. Lett. 2008, 18, 5443.
4. Lebois, E. P.; Bridges, T. M.; Lewis, L. M.; Dawson, E. S.; Kane, A. S.; Kennedy, J.
P.; Xiang, Z.; Jadhav, S. B.; Yin, H.; Meiler, J.; Jones, C. K.; Conn, P. J.; Weaver, C.
D.; Lindsley, C. W. ACS Chem. Neurosci. 2010, 1, 104.
5. Williams, R.; Zhou, Y.; Niswender, C. M.; Luo, Q.; Conn, P. J.; Lindsley, C. W.;
Hopkins, C. R. ACS Chem. Neurosci. 2010, 1, 411; (b) Engers, D. W.; Niswender, C.
M.; Weaver, C. D.; Jadhav, S.; Menon, U.; Zamorano, R.; Conn, P. J.; Lindsley, C.
W.; Hopkins, C. R. J. Med. Chem. 2009, 52, 4115.
6. Felts, A. S.; Lindsley, S. R.; Lamb, J. P.; Rodriguez, A. L.; Menon, U. N.; Jadhav, S.;
Jones, J. K.; Conn, P. J.; Lindsley, C. W.; Emmitte, K. A. Bioorg. Med. Chem. Lett.
2010, 20, 4390.