Development of a highly selective,orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071

Article abstract of DOI:10.1016/j.bmcl.2011.08.084

Herein we report the discovery and SAR of a novel series of M1 agonists based on the MLPCN probe, ML071. From this, VU0364572 emerged as a potent, orally bioavailable and CNS penetrant M1 agonist with high selectivity, clean ancillary pharmacology and enantiospecific activity.

Full text of DOI:10.1016/j.bmcl.2011.08.084

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6451–6455
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of a highly selective, orally bioavailable and CNS penetrant M1
agonist derived from the MLPCN probe ML071
Evan P. Lebois a, Gregory J. Digby a, Douglas J. Sheffler a,b, Bruce J. Melancon a,b,c, James C. Tarr a,b,c
,
Hyekyung P. Cho a,b,c, Nicole R. Miller a,b,c, , Ryan Morrison a,b,c, Thomas M. Bridges a,b, Zixiu Xiang a,
J. Scott Daniels a,b,c, Michael R. Wood a,b,c, P. Jeffrey Conn a,b,c, Craig W. Lindsley a,b,c,
⇑
a Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
c Vanderbilt Specialized Chemistry Center for Probe Development (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:
Herein we report the discovery and SAR of a novel series of M1 agonists based on the MLPCN probe,
ML071. From this, VU0364572 emerged as a potent, orally bioavailable and CNS penetrant M1 agonist
with high selectivity, clean ancillary pharmacology and enantiospecific activity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 August 2011
Revised 15 August 2011
Accepted 17 August 2011
Available online 24 August 2011
Keywords:
Muscarinic acetylcholine receptor 1
mAChR1 (M1)
ML071
Allosteric agonist
The muscarinic acetylcholine receptors, mAChRs or M1–M5, are
members of the class A G protein-coupled receptors (GPCRs) that
mediate a broad range of actions of the neurotransmitter acetyl-
choline (ACh) in the central nervous system and other tissues.1–3
Previous attempts to develop compounds that are highly selective
for M1 have failed because of the high conservation of the orthos-
teric ACh binding site and difficulty in developing truly specific
compounds, not only for M1 (vs M2–M5) but also other biogenic
amine receptors (BARs).4–6 Despite these major shortcomings,
multiple orthosteric M1 ‘preferring’ agonists have provided proof
of concept in Phase II and III clinical trials for both Alzheimer’s dis-
ease (AD) and schizophrenia, generating great enthusiasm for
selective M1 activation.7–14
Current efforts are focused on the selective activation of M1 by
targeting less conserved allosteric sites, and this approach is prov-
ing highly successful for multiple GPCRs.4,5,15,16 Allosteric and/or
bi-topic M1 partial agonists first appeared, such as 1–4, with
improved mAChR selectivity in many instances, but a general lack
of selectivity versus BARs (D2, 5HT2c, 5HT2B, opiate, etc.,) and poor
DMPK properties precluded their utility as tools to probe selective
M1 activation in vivo (Fig. 1).6,17–20 Recently, numerous additional
M1 full and partial agonists have been reported with improved
properties and efficacy in cognition models.21–23 Positive allosteric
modulators (PAMs) from three structural classes, 5–7, have also
been reported, with exquisite selectivity for M1 versus M2–M5
and BARs, allowing limited in vivo proof of concept studies to be
conducted.24–26,28,29,31,32 For all of these PAMs, both DMPK
properties and CNS penetration are barely adequate for in vivo
studies;24–26,28,29,31,32 however, two scaffolds variants of the BQCA
PAM scaffold have overcome the DMPK issues and afforded PAMs
with good properties and CNS exposure.27,30
Based on the need for additional M1 tools, we recently per-
formed a functional M1 HTS of the 65,000 compound MLPCN library
using a high-expressing M1 rat CHO cell line.33,34 From this effort,
we identified M1 agonists, antagonists and PAMs, which were
quickly optimized to afford the M1 selective antagonist ML012
(VU0255035),33 M1 PAMs ML137 (VU0366369)31 and ML169
(VU0405562)32 as well as the M1 agonist ML071 (VU0357017).34
ML071 (8) proved to be a highly selective M1 partial agonist
(EC50 = 200 nM, 81% ACh Max, >30
lary pharmacology (no activity greater than 50% in a 10
l
M vs M2–M5) with clean ancil-
M radioli-
l
⇑
Corresponding author.
gand binding panel of 68 GPCRs, ion channels and transporters,
including the BARs) and favorable DMPK properties and CNS pene-
tration (Fig. 2).31 ML071 demonstrated that selective M1 activation
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
Present address: NIH Chemical Genomics Center, National Institute of Health,
Bethesda, MD, USA.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.084

6452
E. P. Lebois et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6451–6455
O
R
N
HN
N
N
O
N
N
O
O
O
N
O
R =
F
1
2
3
4
, TBPB
, AC-42
, AC-260584
, 77-LH-28-1
O
O
O
N
O
O
O
Me
S
OH
O
N
H
N
N
N
Br
F
N
NMe
F
OMe
5
6
7
, ML169
, BQCA
, ML137
Figure 1. Prototypical ‘M1-preferring’ allosteric (bi-topic) agonists 1–4, and M1 PAM series 5–7.
N-Me
Heterocycle
inactive
inactive
Alt. CO2Rs
Intro.
Cyclic
Constraints
inactive
O
O
H
N
H
N
N
H
R
N
H
N
OEt
O
N
OEt
O
stereogenic center
β-F
N-Me
inactive inactive
8
, ML071
Figure 2. Prior SAR for ML071 and proposal to introduce cyclic constraints.
potentiated NMDA receptor currents, provided a significant in-
crease in soluble APP (sAPP ) in cell culture, and dose-dependently
Max and mAChR selectivity. Efforts now focused on full character-
ization of VU0364572, 17.
a
reversed scopolamine-induced disruption of contextual fear
We then evaluated VU0364572 (17) in a radioligand binding
panel of 68 GPCRs, ion channels and transporters (including all
the BARs),35 and no significant activities were reported (no
conditioning responses.34 However, ML071 also displayed func-
tional D2 antagonism (IC50 = 4.5 lM), which we hoped to eliminate
through chemical optimization. As previously detailed, SAR for
ML071 was shallow, with few modifications tolerated.34 In this
Letter, we describe the introduction of cyclic constraints to impart
improved potency, efficacy and DMPK properties (Fig. 2).
inhibition >30% at 10
ity at hERG (22% at 10
pharmacophore. Furthermore, based on the previously observed
weak functional D2 antagonism of ML071 (D2 IC50 = 4.5 M), we
l
M). Importantly, 17 showed minimal activ-
lM), despite possessing a classical hERG
l
A number of cyclic constraints ((R)- and (S)-3-aminopyrroldines
(9–12), piperazine (13), [2.2.1] (14) and [3.3.0] (15) congeners)
were synthesized (Fig. 3A) and evaluated, affording less than 30%
evaluated 17, and were delighted to find no functional activity at
the D2 receptor (Fig. 4). Based on this, VU0364572 is a highly selec-
tive M1 agonist with exceptionally clean ancillary pharmacology,
and a valuable small molecule tool to dissect the role of direct
and selective M1 activation.1–20
Further in vitro characterization followed, evaluating the ability
of 17 to shift APP processing towards the nonamyloidogenic path-
way. Employing our standard model20,22,28,29 in TREx293-hM1
M1 activation at 10 lM (Fig. 3B). However, the (R)-aminopiperidine
constraint 17 (VU0364572) afforded full activation of M1, while the
(S)-enantiomer 16 was inactive, providing the first reported exam-
ple of enantioselective M1 activation. VU0364572 proved to be
highly selective for M1 (Fig. 3C) with an EC50 of 110 nM and
ꢀ95% ACh Max.
cells, carbachol (CCh) (10
soluble APP (sAPP ), whereas an identical concentration of 17 pro-
. Based on this
lM) affords a significant increase in
This finding led us to synthesize libraries of analogs around
both 16 and 17 wherein we varied the amide moiety; interestingly,
a
vides a more robust increase (ꢀ3-fold) in sAPP
a
all (S)-enantiomers 16 were inactive (M1 EC50s >10
l
M). Analogs
data, selective activation of M1, via 17, may have a disease modify-
17 were synthesized according to Scheme 1. As shown in Table 1,
ing role in AD.
SAR was shallow, as with ML071,34 with only 12 of 36 analogs pos-
Activation of NMDA receptor currents by M1 is postulated to
play a critical role in the cholinergic regulation of cognitive func-
tion and circuitry that underlie the efficacy of mAChR agonists in
sessing M1 potencies below 5
lM; moreover, 17 proved to be the
best compound within this series in terms of M1 potency, ACh

E. P. Lebois et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6451–6455
6453
Figure 3. (A) Structures of cyclic constrained analogs of 8; (B) 10
(17).
lM M1 single point screen of cyclic constraint variants of ML071; (C) Full CRCs at M1–M5 for VU0364572
O
O
R
H2N
a,b
N
N
N
H
c
N
N
N
OEt
OEt
O
OEt
O
O
18
19
20
Scheme 1. Reagents and conditions: (a) (R)-3-amino-3-N-Boc-piperidine, NaBH(OAc)3, DCE, 95%; (b) HCl, dioxane, rt, 96%; (c) RCOCl, DIEA, DCM, rt, 65–95%.
schizophrenia (the NMDA receptor hypofunction hypothesis of
schizophrenia)36 and AD. As shown in Figure 5, VU0364572 (17),
was found to potentiate NMDA receptor currents in hippocampal
CA1 pyramidal cells, further validating selective M1 activation as
a means to promote synaptic plasticity.
The in vitro data was tremendously exciting, prompting the
evaluation of 17 in our tier 1 DMPK battery. Compound 17
displayed low plasma protein binding for both human (fu = 5.8%)
and rat fu = 14.9%) and had a clean CYP profile (3A4, 2C9, 1A2
tantly, 17 was orally bioavailable with a %F of 37 (AUCIV = 1.1
lg
h/mL, AUCPO = 4.2 g h/mL). In parallel, we performed an oral plas-
l
ma:brain level (PBL) study with 17 in male Sprague–Dawley rats
(Table 2). At a dose of 10 mg/kg with a 90 min endpoint, 17
achieved an average BrainAUC/PlasmaAUC of 1.35, providing excel-
lent CNS exposure.
As it became time to profile 17 on human M1–M5, our research
team had moved away from the high-expressing HTS lines and
developed both rat and human M1–M5 with expression more
closely resembling native expression levels. In these new cell
lines, both 17 and ML071 experienced an ꢀ10-fold right shift in
and 2D6; IC50 >25 lM). Intrinsic clearance experiments (rat
CLINT = 23.4 mL/min/kg and human CLINT = 11.2 mL/min/kg) sug-
gested 17 would be a low to moderate clearance compound, and
rat PK confirmed a good in vitro/in vivo correlation. A standard
rat IV (1 mg/kg)/PO (10 mg/kg) study found 17 to possess a CL of
14.7 mL/min/kg, with a Vss of 0.98 L/kg and a t1/2 of 46 min. Impor-
potency (EC50s of 1.3 lM and 2.3 lM, respectively) with slightly
lower ACh Max, yet still remained highly selective (M2–M5
EC50s >30 M). As M1 expression levels vary amongst neuronal
tissues and brain regions, compounds such as 17 may behave as
l

6454
E. P. Lebois et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6451–6455
Table 1
Structures and activities of M1 agonist analogs 20a–k
OEt
N
N
O
O
R
NH
20
M)
Compd
R
M1EC50
0.2
(l
ACh Maxa
81
(
lM)
M2–M5 EC50sa
>30
(lM)
a
8
17
0.11
0.06
96
77
>30
>10
20a
F
20b
20c
20d
0.13
0.14
0.25
91
92
91
>10
>10
>10
F
MeO
F
F
20e
20f
0.31
0.89
84
41
>10
>10
20g
20h
0.69
1.3
44
61
>10
>10
S
20i
0.96
63
>10
MeO
20j
2.6
5.0
57
35
>10
>10
Cl
20k
a
Average of at least three determinations in our rat high-expressing CHO cell line.
Figure 4. (A) CRC for ML071 for D2 antagonism, affording an IC50 of 4.5 lM; (B) CRC for VU0364572 for D2 antagonism, affording an IC50 >30 lM.
full agonists in one population and as weak, partial agonists in
another. The ramifications of this, and further in depth in vitro/
in vivo pharmacological studies are in progress and will be re-
ported shortly.37
In summary, the chemical lead optimization of the MLPCN M1
agonist probe ML071 (VU0357017), led to the discovery of
VU0364572 (17), an M1 agonist with high selectivity (vs M2–M5
as well as the BARs), exceptional PK and brain exposure, robust ef-
fects on APP processing and potentiation of NMDA receptor cur-
rents and enantiospecific M1 activation. Further in depth in vitro/
in vivo pharmacological studies with VU0364572 (17) are in pro-
gress and will be reported shortly.

E. P. Lebois et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6451–6455
6455
12. Caccamo, A.; Oddo, S.; Billings, L. M.; Green, K. N.; Martinez-Coria, H.; Fisher,
A.; LaFerla, F. M. Neuron 2006, 49, 671.
13. Raedler, T. J.; Bymaster, F. P.; Tandon, R.; Copolov, D.; Dean, B. Mol. Psych. 2007,
12, 232.
14. Fisher, A. Neurodegen. Dis. 2008, 5, 237.
15. Lewis, J.; Lebois, E. P.; Lindsley, C. W. Curr. Opin. Chem. Biol. 2008, 12, 269.
16. Bridges, T. M.; Lindsley, C. W. ACS Chem. Biol. 2008, 3, 530.
17. Langmead, C. J.; Fry, V. A. H.; Forbes, I. T.; Branch, C. L.; Christopoulos, A. C.;
Wood, M. D.; Herdon, H. J. Mol. Pharm. 2006, 69, 236.
18. Langmead, C. J.; Austin, N. E.; Branch, C. L.; Brown, J. T.; Buchanan, K. A.; Davies,
C. H.; Forbes, I. T.; Fry, V. A. H.; Hagan, J. J.; Herdon, J. J.; Jones, G. A.; Jeggo, R.;
Kew, J. N. C.; Mazzali, A.; Melarange, R.; Patel, N.; Pardoe, J.; Randall, A. D.;
Roberts, C.; Roopun, A.; Starr, K. R.; Teriakidis, A.; Wood, M. D.; Whittington,
M.; Wu, Z.; Watson, J. Br. J. Pharmacol. 2008, 154, 1104.
19. Bradley, S. R.; Lameh, J.; Ohrmund, L.; Son, T.; Bajpai, A.; Nguyen, D.; Friberg,
M.; Burstein, E. S.; Spalding, T. A.; Schiffer, H. H.; Tabatabaei, A.; McFarland, K.;
Davis, R. E.; Bonhaus, D. W. Neuropharmacology 2010, 58, 365.
20. Jones, C. K.; Brady, A. E.; Davis, A. A.; Xiang, Z.; Bubser, M.; Tantawy, M. N.;
Kane, A. S.; Bridges, T. M.; Kennedy, J. P.; Bradley, S. R.; Peterson, T. E.; Ansari,
M. W.; Baldwin, R. M.; Kessler, R. M.; Deutch, A. Y.; Lah, J. J.; Levey, A. I.;
Lindsley, C. W.; Conn, P. J. J. Neurosci. 2008, 28, 10422.
21. Watt, M. L.; Schober, D. A.; Hitchcock, S.; Liu, B.; Chesterfield, A. K.; McKinzie,
D.; Felder, C. C. J. Pharm. Exp. Ther. 2011, 338, 622.
22. Budzik, B.; Garzya, V.; Shi, D.; Walker, G.; Wooley-Roberts, M.; Pardoe, J.; Lucas,
A.; Tehan, B.; Rivero, R. A.; Langmead, C. J.; Watson, J.; Wu, Z.; Forbes, I. T.; Jin, J.
ACS Med. Chem. Lett. 2010, 1, 244.
23. Johnson, D. J.; Forbes, I. T.; Watson, S. P.; Garzya, V.; Stevenson, G. I.; Walker, G.
R.; Mudhar, H. S.; Flynn, S. T.; Wyman, P. A.; Smith, P. A.; Murkitt, G. S.; Lucas,
A. J.; Mookherjee, C. R.; Watson, J. M.; Garlton, J. E.; Bradford, A. M.; Brown, F.
Bioorg. Med. Chem. Lett. 2010, 20, 5434.
Figure 5. VU0364572 potentiates NMDA receptor currents in hippocampal CA1
pyramidal cells. (A) Representative whole cell traces of NMDA-evoked currents and;
(B) time course of normalized amplitude of NMDAR currents before, during and
after application of 30 lM VU0364572 (17). Notably, even after washout, the
potentiation persists for 10 min. Error bars represent mean SEM for five
independent determinations.
24. Ma, L.; Seager, M.; Wittman, M.; Bickel, N.; Burno, M.; Jones, K.; Graufelds, V.
K.; Xu, G.; Pearson, M.; McCampbell, A.; Gaspar, R.; Shughrue, P.; Danzinger, A.;
Regan, C.; Garson, S.; Doran, S.; Kreatsoulas, C.; Veng, L.; Lindsley, C. W.; Shipe,
W.; Kuduk, S.; Jacobson, M.; Sur, C.; Kinney, G.; Seabrook, G. R.; Ray, W. J. Proc.
Natl. Acad. Sci. U.S.A. 2009, 106, 15950.
25. Shirey, J. K.; Brady, A. E.; Jones, P. J.; Davis, A. A.; Bridges, T. M.; Jadhav, S. B.;
Menon, U.; Christain, E. P.; Doherty, J. J.; Quirk, M. C.; Snyder, D. H.; Levey, A. I.;
Watson, M. L.; Nicolle, M. M.; Lindsley, C. W.; Conn, P. J. J. Neurosci. 2009, 29,
14271.
Table 2
10 mg/kg Oral plasma:brain level study with 17
Dose (mg/kg)
Animal
Plasma (
lM)
Brain (
lM)
Brain:Plasma
10
10
1
2
1.45
1.62
2.23
1.89
1.54
1.17
26. 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.
27. Kuduk, S. D.; Chang, R. K.; Di Marco, C. N.; Ray, W. J.; Ma, L.; Wittman, M.;
Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M.
T. ACS Med. Chem. Lett. 2010, 1, 263.
28. Kuduk, S. D.; Di Marco, C. N.; Chang, R. K.; Ray, W. J.; Ma, L.; Wittman, M.;
Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M.
T. Bioorg. Med. Chem. Lett. 2010, 20, 2533.
Acknowledgments
The authors thank the NIH and NIMH for support of our M1
muscarinic program (1RO1MH082867-01). Vanderbilt is a Special-
ized Chemistry Center within the MLPCN (U54MH084659), and
ML071 is an MLPCN probe, freely avaialble upon request.
29. Kuduk, S. D.; Chang, R. K.; Di Marco, C. N.; Ray, W. J.; Ma, L.; Wittman, M.;
Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M.
T. Bioorg. Med. Chem. Lett. 2011, 21, 1710.
References and notes
30. Kuduk, S. D.; Chang, R. K.; Di Marco, C. N.; Pitts, D. R.; Greshock, T. J.; Ma, L.;
Wittman, M.; Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.;
Bilodeau, M. T.; Ray, W. J. J. Med. Chem. 2011, 54, 4773. and references cited
therein.
31. Bridges, T. M.; Kennedy, J. P.; Cho, H. P.; Conn, P. J.; Lindsley, C. W. Bioorg. Med.
Chem. Lett. 2010, 20, 1972.
32. Reid, P. R.; Bridges, T. M.; Sheffler, D. A.; Cho, H. P.; Lewis, L. M.; Days, E.;
Daniels, J. S.; Jones, C. K.; Niswender, C. M.; Weaver, C. D.; Conn, P. J.; Lindsley,
C. W.; Wood, M. R. Bioorg. Med. Chem. Lett. 2011, 21, 2697.
33. Sheffler, D. J.; Williams, R.; Bridges, T. M.; Lewis, L. M.; Xiang, Z.; Zheng, F.;
Kane, A. S.; Byum, N. E.; Jadhav, S.; Mock, M. M.; Zheng, F.; Lewis, L. M.; Jones, C.
K.; Niswender, C. M.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W.; Conn, P. J. Mol.
Pharmacol. 2009, 76, 356.
34. Lebois, E. P.; Bridges, T. M.; Dawson, E. 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.
35. For information on the Ricerca Lead Profiling Screen, see: http://
www.ricerca.com.
36. Lindsley, C. W.; Shipe, W. D.; Wolkenberg, S. E.; Theberge, C. R.; Williams, D. L.,
Jr.; Sur, C.; Kinney, G. G. Curr. Top. Med. Chem. 2006, 8, 771.
37. Manuscripts in preparation.
1. Levey, A. I. Life Sci. 1993, 52, 441.
2. Abrams, P.; Andersson, K. E.; Buccafusco, J. J.; Chapple, C.; Chet de Groat, W.;
Fryer, A. D.; Kay, G.; Laties, A.; Nathanson, N. M.; Pasricha, P. J.; Wein, A. Br. J.
Pharmacol. 2006, 148, 565.
3. Volpicelli, L. A.; Levey, A. I. Prog. Brain Res. 2004, 145, 59.
4. Conn, P. J.; Jones, C. K.; Lindsley, C. W. Trends Pharmacol. Sci. 2009, 30, 148.
5. Conn, P. J.; Christopoulos, A.; Lindsley, C. W. Nat. Rev. Drug Disc. 2009, 8, 41.
6. Heinrich, J. N.; Butera, J. A.; Carrick, T.; Kramer, A.; Kowal, D.; Lock, T.; Marquis,
K. L.; Pausch, M. H.; Popiolek, M.; Sun, S. C.; Tseng, E.; Uveges, A. J.; Mayer, S. C.
Eur. J. Pharmacol. 2009, 605, 53.
7. Shekhar, A.; Potter, W. Z.; Lightfoot, J.; Lienemann, J.; Dube, S.; Mallinckrodt, C.;
Bymaster, F. P.; McKinzie, D. L.; Felder, C. C. Am. J. Psychol. 2008, 165, 1033.
8. Mirza, N. R.; Peters, D.; Sparks, R. G. C. N. S. Drug Rev. 2003, 9(2), 159.
9. Sur, C.; Mallorga, P. J.; Wittmann, M.; Jacobson, M. A.; Pascarella, D.; Williams, J.
B.; Brandish, P. E.; Pettibone, D. J.; Scolnick, E. M.; Conn, P. J. PNAS 2003, 100,
13674.
10. Pakrasi, S.; Colloby, S. J.; Firbank, M. J.; Perry, E. K.; Wyper, D. J.; Owens, J.;
McKeith, I. G.; Williams, E. D.; O’Brien, J. T. J. Neurol. 2003, 254, 907.
11. Bodick, N. C.; Offen, W. W.; Levey, A. I.; Cutler, N. R.; Gauthier, S. G.; Satlin, A.;
Shannon, H. E.; Tollefson, G. D.; Rasmussen, K.; Bymaster, F. P.; Hurley, D. J.;
Potter, W. Z.; Paul, S. M. Arch. Neurol. 1997, 54, 465.