Novel substituted 4-phenyl-[1,3]dioxanes: Potent and selective orexin receptor 2 (OX2R) antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.06.032

Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX ₁R and OX₂R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX₂R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4- phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX₂R with a pK_i of 8.3, has a pK_b of 7.9, and is 600-fold selective for the OX₂R over the OX₁R.

Full text of DOI:10.1016/j.bmcl.2004.06.032

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4225–4229
Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective
orexin receptor 2 (OX2R) antagonists
Laura C. McAtee, Steven W. Sutton,* Dale A. Rudolph, Xiaobing Li, Leah E. Aluisio,
Victor K. Phuong, Curt A. Dvorak, Timothy W. Lovenberg, Nicholas I. Carruthers
and Todd K. Jones
Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA
Received 16 April 2004; revised 7 June 2004; accepted 7 June 2004
Available online
Abstract—Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known
G-protein coupled receptors (OX1R and OX2R). In addition to other biological functions, the orexin-2 receptor is thought to be an
important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX2R antagonists consisting of
substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-
[1,3]dioxan-5-yl)-urea, which is bound by the OX2R with a pKi of 8.3, has a pKb of 7.9, and is 600-fold selective for the OX2R over
the OX1R.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
narcolepsy appears to be linked to deficient orexin sig-
naling, most likely related to immune ablation of
orexinergic neurons in the lateral hypothalamus.17;18
Herein we report on a novel series of nonpeptidic, small
molecule antagonists for the orexin-2 receptor. These
compounds are among the most potent and selective
small molecule antagonists for this receptor to date and
should prove useful for further elucidating the role of
the OX2R receptor.19–22
In 1998 two research groups, working independently
and using different methods, discovered two neuropep-
tides, orexin A and orexin B.1;2 The two neuropeptides,
which are processed from the same gene and are pro-
duced by neurons in the lateral hypothalamus are also
known as the hypocretins.1;2 The orexin neuropeptides
play a role in a variety of biological functions including
the sleep/wake cycle, feeding behavior, regulation of
gastric acid secretion, metabolic rate, and blood pres-
sure.3–10 Two receptors for orexin A and orexin B were
also identified and they are known as orexin 1 (OX1R)
and orexin 2 (OX2R).2 While the orexin-2 receptor
binds both neuropeptides with similar affinity, the
orexin-1 receptor binds orexin A with slightly higher
affinity than orexin B. Several reports of antagonists for
the orexin-1 receptor have already appeared in the lit-
erature and suggest that this receptor is closely related
to feeding, metabolism, and digestive function.11–16 Re-
cent data suggests that the orexin-2 receptor is associ-
ated with the sleep/wake cycle and that mutations to
this receptor are related to canine narcolepsy.5 Human
2. Chemistry
A high throughput screen (HTS) of our chemical library
identified several hits including the novel urea-containing
4-phenyl-[1,3]dioxane, 1, as an antagonist of the human
orexin-2 receptor. Compound 1, 1-(2-bromo-phenyl)-
3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea,
as a single enantiomer was also fairly selective for the
O
O
O
N
H
N
H
Br
* Corresponding author. Tel.: +1-858-784-3093; fax: +1-858-450-2040;
e-mail: ssutton@prdus.jnj.com
1
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.032

4226
L. C. McAtee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4225–4229
orexin-2 receptor (pKi OX2R ¼ 7.0, OX1R ¼ 5.7).23
Compound 1 and related analogs were readily synthe-
sized by reacting commercially available isocyanates with
amine 2 (Scheme 1).24 In addition, Suzuki cross-coupling
reactions25;26 could be successfully performed on several
of the resulting products, such as 4, to provide com-
pounds with a diverse range of functionality including
heterocyclic substituents. In an effort to further increase
receptor binding affinity, we initially chose to explore a
variety of substituents with a range of different electronic
properties at one or more positions on the phenyl ring
arising from the isocyanate (Tables 1 and 2).27
We were also interested in identifying, which changes, if
any, would be tolerated in the central urea portion of the
molecule. Traditional urea replacement analogs such as
those with amide, thiourea, and cyanoguanidine func-
tionalities were synthesized. Thioureas were synthesized
in the same manner as the urea analogs except that an
isothiocyanate was used in place of an isocyanate in the
reactions. Amides and carbamates were synthesized by
reacting amine 2 with an acyl chloride or phenyl chlo-
roformate in the presence of triethylamine. Cyanogua-
nidines were synthesized in two steps starting from
diphenylcyanocarbonimidate and an appropriately
substituted aniline (Scheme 2).
O
O
O
R
a
O
O
H2N
N
H
N
H
3. Biological results and discussion
Compounds 1 and 6–34 were evaluated for biological
activity. Determination of receptor binding character-
istics of the compounds was accomplished using
adherent, cultured recombinant cells, and radioiodin-
ated orexin A.28 In addition, compound antagonism was
demonstrated using a functional assay of intracellular
Caþþ responses in cells expressing OX2R.29 Agonist
binding to orexin receptors elevates the intracellular free
calcium ion concentration through the activation of a
Gq protein and the opening of voltage-activated plasma
membrane calcium channels.30 This effect was moni-
tored using the fluorescent Caþþ indicator Fluo-3 AM
(TefLabs, Austin, TX) and the Molecular Devices
2
3
O
O
O
O
b
I
O
O
N
H
N
H
N
H
N
H
heterocycle
5
4
Scheme 1. Reagents and conditions: (a) isocyanate (R-PhNCO) and
pentane, ꢀ80–90%; (b) tetrakis(triphenylphosphine) palladium(0),
ethylene glycol dimethyl ether, boronic acid, aqueous sodium car-
bonate ꢀ50%.
Table 1. Orexin receptor binding affinities of 4-phenyl-[1,3]dioxanes
R4
R3
R2
R5
O
O
O
N
N
H
H
R1
Compounda
R1
R2
R3
R4
R5
OX2Rb
OX1Rb
Selectivityc
1
Br
H
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
7.0 (6.8–7.1)
6.3 (6.1–6.4)
6.0 (5.8–6.1)
6.6 (6.3–7.0)
8.3 (8.0–8.6)
7.7 (7.6–7.9)
8.2 (7.9–8.6)
7.4 (7.3–7.5)
7.2 (7.0–7.3)
6.9 (6.7–7.0)
7.2 (7.1–7.3)
<5.3
5.7 (5.3–6.1)
<5.0
<5.0
20
6
H
>20
>9
7
H
H
8
H
Br
Br
Cl
Br
Br
H
<5.0
>40
600
100
>900
200
>80
>70
>80
>2
9
Br
Cl
5.5 (5.3–5.8)
5.6 (5.4–5.8)
<5.3
10
11
12
13
14
15
16
17
18
19
20
21
22
Cl
Me
Cl
<5.0
<5.3
Me
Cl
Me
H
<5.0
<5.3
Cl
H
<5.0
<5.3
I
Cl
H
7.1 (7.0–7.3)
7.1 (7.0–7.2)
6.4 (6.1–6.6)
5.6 (5.3–5.9)
7.0 (6.9–7.1)
5.6 (5.4–5.7)
>70
>100
>20
>4
H
<5.0
<5.0
F
H
OMe
CF3
i-Pr
H
<5.0
<5.0
H
>100
>4
H
<5.0
a See Ref. 27.
b pKi with 95% confidence intervals in parenthesis.
c Selectivity ¼ (OX1R Ki/OX2R Ki).

L. C. McAtee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4225–4229
Table 2. Orexin receptor binding affinities of 4-phenyl-[1,3]dioxanes
4227
O
O
O
N
H
N
H
R1
Compounda
R1
OX2Rb
OX1Rb
Selectivityc
23
24
25
26
27
28
2-Thiophene
3-Thiophene
Phenyl
7.3 (7.1–7.4)
7.1 (7.1–7.2)
7.0 (6.7–7.3)
7.6 (7.5–7.7)
6.5 (6.4–6.6)
7.1 (7.0–7.2)
6.0 (5.9–6.1)
5.7 (5.5–5.9)
6.3 (6.2–6.4)
6.9 (6.7–7.0)
<5.3
20
30
4
2-Chlorophenyl
3-Pyridyl
3-Chlorophenyl
5
>20
6
6.3 (6.2–6.4)
a See Ref. 27.
b pKi with 95% confidence intervals in parenthesis.
c Selectivity ¼ (OX1R Ki/OX2R Ki).
11 were also fairly selective for the orexin-2 receptor
over the orexin-1 receptor with each possessing an
OX1R pKi of 6 5.5. In addition to halogen substituents,
it should be noted that chlorophenyl substituents and
heterocycles such as thiophenes were also well tolerated
in the R1 position of the phenyl ring (Table 2). The
compounds in Table 2 indicate that there is probably
room for variation in this region of the molecule unlike
the central urea portion of the molecule, which is much
more conserved. As can be observed in Table 3, even
simple single atom substitutions resulted in a significant
drop in binding affinity. Replacing the oxygen atom of 1
or 10 with a sulfur atom in 29 and 30, respectively, yields
a 3–10-fold drop in activity.
R4
R1
R4
R1
CN
N
R3
R2
R5
R3
R2
R5
c
NH2
N
H
OPh
R4
R1
CN
N
R3
R2
R5
O
d
O
N
H
N
H
Scheme 2. Reagents and conditions: (c) diphenylcyanocarboimidate
and acetonitrile ꢀ22%; (d) amine 2 and acetonitrile ꢀ23%.
Altering the central urea to an amide (31 and 33) or
carbamate (32) reduced the OX2R affinity more than
10-fold and eliminated any OX1R affinity for the com-
pounds. Replacing the urea moiety with a cyanoguani-
dine, 34, also resulted in a substantial drop in activity.
These results were somewhat disappointing since many
of the active compounds in this series possessed poor
aqueous solubility. The urea moiety was regarded as the
culprit for this poor aqueous solubility as is often the
case and efforts are continuing to find a suitable
replacement for this functionality.
(Sunnyvale, CA) FLIPR instrument. The pKB was
determined after Y.-C. Cheng and W. H. Prusoff31 using
the formula below:
pKB ¼ ꢁ logðIC50=ð1 þ ðagonist=EC50ÞÞÞ
The presence of a halogen atom such as chlorine, bro-
mine or iodine in the ortho-position (R1) was very
important for obtaining significant binding affinity to
the orexin-2 receptor. By comparison, the unsubstituted
analog, 6, was significantly less active. After fully
exploring numerous mono-substituted analogs, it was
apparent that the most potent compounds were ob-
tained with an electron-withdrawing or alkyl (preferably
methyl) substituent on the phenyl ring. This same pref-
erence for electron-withdrawing and methyl substituents
was also observed in analogs with multiple substitution
patterns on the phenyl ring.
In addition to testing orexin receptor binding, the 4-
phenyl 1,3-dioxanes were tested for receptor specificity
and antagonism. Receptor specificity was demonstrated
for compounds 1, 9, 17, and 26 in a CEREP ExpresS-
Profile (CEREP, Redmond, WA) screen of 50 receptors,
ion channels and transporters. These compounds ap-
plied at 10 lM failed to show >20% inhibition in any of
the CEREP assays, with the exception of 9 (which dis-
played <40% inhibition in the K opiate, NPY1, and
Neurokinin 3 receptor binding assays, but was otherwise
inert). Antagonism of the OX2R was verified using a
functional assay. Examples of data from the functional
assay are shown in Table 4 above. Active compounds
were also tested for agonism in a manner similar to the
pKB assay (compound was tested without preincubation
As shown in Table 1, the 2,4-disubstituted and 2,5-
disubstituted positions were optimal for achieving
activity as exemplified by 9, 11, and 13 with pKi values
of 8.3, 8.2, and 7.2, respectively, at the OX2R receptor.
In contrast, the 2,6-disubstitution pattern as illustrated
by compound 16 was the most unfavorable and dra-
matically diminished binding affinity. Compounds 9 and

4228
L. C. McAtee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4225–4229
Table 3. Orexin receptor 2 binding affinities of 4-phenyl-[1,3]dioxanes
R3
O
W
O
Z
N
H
R1
Compounda
R1
R3
W
Z
OX2Rb
OX1Rb
Selectivityc
29
30
31
32
33
34
Br
Cl
Cl
Cl
Br
Br
H
S
NH
NH
––
6.4 (6.3–6.5)
6.7 (6.6–6.8)
6.7 (6.4–7.1)
5.8 (5.6–5.9)
5.8 (5.7–6.0)
5.9 (5.6–6.2)
<5.0
<5.0
<5.0
<5.0
<5.0
<5.0
>30
>50
>50
>6
Cl
Cl
H
S
O
O
O
H
Me
O
N-CN
CH2
NH
>7
>8
a See Ref. 27.
b pKi with 95% confidence intervals in parenthesis.
c Selectivity ¼ (OX1R Ki/OX2R Ki).
Table 4. Examples of antagonism of orexin receptor 2 by 4-phenyl-
[1,3]dioxanes
3. Asahi, S.; Egashira, S.; Matsuda, M.; Iwaasa, H.; Kana-
tani, A.; Ohkubo, M.; Ihara, M.; Sakurai, T.; Morishima,
H. Pept. Sci. 1999, 36, 37.
4. Takahashi, N.; Okumura, T.; Yamada, H.; Kohgo, Y.
Biochem. Biophys. Res. Commun. 1999, 254, 623.
5. Lin, L.; Faraco, J.; Li, R.; Kadotani, H.; Rogers, W.; Lin,
X.; Qiu, X.; De Jong, P. J.; Nishino, S.; Mignot, E. Cell
1999, 98, 365.
R3
O
O
O
N
H
N
H
R1
6. Chemelli, R. M.; Willie, J. T.; Sinton, C. M.; Elmquist, J.
K.; Scammell, T.; Lee, C.; Richardson, J. A.; Williams,
S. C.; Xiong, Y.; Kisanuki, Y.; Fitch, T. E.; Nakazato, M.;
Hammer, R. E.; Saper, C. B.; Yanagisawa, M. Cell 1999,
98, 437.
7. Kirchgessner, A. L.; Liu, M.-T. Neuron 1999, 24,
941.
8. Samson, W. K.; Gosnell, B.; Chang, J.-K.; Resch, Z. T.;
Murphy, T. C. Brain Res. 1999, 831, 248.
Compound
R1
R3
OX2Ra
1
Br
Cl
I
H
H
H
Br
Cl
6.3 (6.1–6.5)
6.0 (5.9–6.2)
6.5 (6.3–6.7)
7.9 (6.0–9.8)
7.0 (6.3–7.7)
18
17
9
Br
Cl
10
a pKB values with 95% confidence intervals in parenthesis.
9. Shirasaka, T.; Nakazato, M.; Matsukura, S.; Takasaki,
M.; Kannan, H. Am. J. Physiol. 1999, 277, R1780.
10. Chen, C. T.; Hwang, L. L.; Chang, J. K.; Dun, N. J. Am.
J. Physiol. 2000, 278, R692.
11. Haynes, A. C.; Jackson, B.; Chapman, H.; Tadayyon, M.;
Johns, A.; Porter, R. A.; Arch, J. R. S. Regul. Pept. 2000,
96, 45.
12. Rodgers, R. J.; Halford, J. C.; Nunes de Souza, R. L.;
Canto de Souza, A. L.; Piper, D. C.; Arch, J. R.; Upton,
N.; Porter, R. A.; Johns, A.; Blundell, J. E. Eur. J.
Neurosci. 2001, 13, 1444.
13. Smart, D.; Sabido-David, C.; Brough, S. J.; Jewitt, F.;
Johns, A.; Porter, R. A.; Jerman, J. C. Br. J. Pharmacol.
2001, 132, 1179.
or addition of the orexin agonist) and all active com-
pounds were antagonists.
In conclusion, we have identified several potent and
selective antagonists for the orexin-2 receptor. These
antagonists may be useful in further elucidating the role
played by the orexin-2 receptor and possibly in future
treatments of sleep/wake disorders.
14. Coulton, S.; Johns, A.; Porter, R. PCT WO 00/47580,
August 17, 2000, 31pp.
References and notes
15. Johns, A; Porter, R. PCT W0 00/47576, August 17, 2000;
29 pp.
1. De Lecea, L.; Kilduff, T. S.; Peyron, C.; Gao, X. B.;
Foye, P. E.; Danielson, P. E.; Fukuhara, C.; Battenberg,
E. L. F.; Gautvik, V. T.; Bartlett, F. S., II; Frankel, W. N.;
Van Den Pol, A. N.; Bloom, F. E.; Gautvik, K. M.;
Sutcliffe, J. G. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
322.
2. Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.;
Chemelli, R. M.; Tanaka, H.; Williams, S. C.; Richardson,
J. A.; Kozlowski, G. P.; Wilson, S.; Arch, J. R. S.;
Buckingham, R. E.; Haynes, A. C.; Carr, S. A.; Annan, R.
S.; McNulty, D. E.; Liu, W.-S.; Terrett, J. A.; Elshour-
bagy, N. A.; Bergsma, D. J.; Yanagisawa, M. Cell 1998,
92, 573.
16. Porter, R. A.; Chan, W. N.; Coulton, S.; Johns, A.;
Hadley, M. S.; Widdowson, K.; Jerman, J. C.; Brough, S.
J.; Coldwell, M.; Smart, D.; Jewitt, F.; Jeffrey, P.; Austin,
N. Bioorg. Med. Chem. Lett. 2001, 11, 1907.
17. Mignot, E.; Lin, L.; Rogers, W.; Honda, Y.; Qiu, X.; Lin,
X.; Okun, M.; Hohjoh, H.; Miki, T.; Hsu, S. H.; Leffell,
M. S.; Grumet, F. C.; Fernandez-Vina, M.; Honda, M.;
Risch, N. Am. J. Hum. Genet. 2001, 68, 686.
18. Mignot, E.; Thorsby, E. N. Engl. J. Med. 2001, 344,
692.
19. Branch, C. L.; Johnson, C. N.; Stemp, G.; Thewlis, K.
PCT WO 01/96302 A1, December 20, 2001; 34 pp.

L. C. McAtee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4225–4229
4229
20. Koberstein, R.; Aissaoui, H.; Bur, D.; Clozel, M.; Fischli,
W.; Jenck, F.; Mueller, C.; Nayler, O.; Sifferlen, T.;
Trieber, A.; Weller, T. Chimia 2003, 57, 270.
21. Fischli, W.; Clozel, M; Weller, J.; Koberstein, R.; Aissa-
oui, H; Sifferlen, J. PCT WO 02/051232 A2, July 4, 2002;
55 pp.
22. Hirose, M.; Egashira, S.; Goto, Y.; Hashihayata, T.;
Ohtake, N.; Iwaasa, H.; Hata, M.; Fukami, T.; Kanatani,
A.; Yamada, K. Bioorg. Med. Chem. Lett. 2003, 13,
4497.
23. This was confirmed via preparation and evaluation of the
individual enantiomers. The 4R,5R enantiomer was inac-
tive at both orexin-1 and orexin-2 receptors.
and caution should be used. In cases where a precipitate is
not observed or the precipitate is not of sufficient purity,
the reaction mixture was evaporated and purified by
column chromatography (hexanes/ethyl acetate) to yield
the desired product.
28. Radioligand binding assays were performed using clonal
CHO-K1 cells expressing the orexin receptor grown on
opaque, white 96-well tissue culture plates pretreated with
poly-D-lysine (Bio-Coat plates, Becton Dickinson, Frank-
lin Lakes, NJ). Binding reactions were performed in
0.1 mL of Dulbecco’s phosphate buffered saline containing
0.1% w/v bovine serum albumin, 105 cpm 125I-orexin A at
2200 Ci/mmol and test compounds or controls. After a 90–
120 min incubation at room temperature, the assay was
terminated by aspirating the liquid from the wells, washing
the wells with iced binding buffer, aspirating the wells dry,
adding 50 lL/well scintillation cocktail (MicroScint 40,
Packard Biosciences, Meriden CT), and counting the
plate(s) in a Packard TopCount scintillation counter. Data
were analyzed using GraphPad Prizm software to calcu-
late Ki values and 95% confidence intervals (N ¼ 3 assays),
which are shown in parentheses in the tables.
24. Nordin, I. C.; Thomas, J. A. Tetrahedron Lett. 1984, 25,
5723.
25. Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui,
M. A.; Snieckus, V.; Josephy, P. D. J. Org. Chem. 1991,
56, 3763.
26. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
27. All compounds in Tables 1–3 were characterized by 1H
NMR and MS data. A general procedure for the prepa-
ration of urea analogs is illustrated by the synthesis of
compound 11. To a stirred or shaken solution of 157 mg
(0.76 mmol) of amine 2 in pentane (3.5 mL) was added
dropwise a solution of 169 mg (0.73 mmol) of 4-bromo-2-
chlorophenyl isocyanate in CH2Cl2 (0.7 mL). A white
precipitate was observed within 2 h, collected, rinsed with
pentane, and dried under vacuum to yield 280 mg (88%) of
29. For screening purposes compounds were tested at a single
dose (10 lM) to determine the percent inhibition of
intracellular Caþþ signaling compared to a 100 nM orexin
agonist stimulus. Antagonism was further evaluated by
calculating pKB values for compounds with a pKi at the
OX2R of greater than 6.3. This was accomplished by
determining the EC50 of orexin B and comparing the IC50
values determined from dilutions of antagonist com-
pound(s), all on a single 96-well Viewplate of cells loaded
with Fluo-3 AM. GraphPad Prism was used to calculate
EC50 and IC50 values for each plate and to calculate 95%
confidence intervals for the resulting pKB values (N ¼ 3
triplicate assays).
1
11. H NMR (CD3OD) 7.67 (d, J ¼ 9:0 Hz, 1H), 7.46 (d,
J ¼ 2:0 Hz, 1H), 7.40 (m, 2H), 7.26 (m, 4H), 5.30 (d,
J ¼ 2:0 Hz, 1H), 4.39 (dd, J ¼ 12:0 Hz, J ¼ 2:0 Hz, 1H),
4.02 (m, 1H), 3.82 (dd, J ¼ 12:0 Hz, J ¼ 2:0 Hz, 1H), 1.62
(s, 3H), 1.58 (s, 3H). Elemental analysis calcd for
C19H20BrClN2O3: C, 51.90; H, 4.58; N, 6.37. Found C,
52.24; H, 4.76; N, 6.33. MS (M + Na)þ ¼ 461, 463. When
possible, pentane was used to dissolve the required
isocyanate rather than CH2Cl2. In cases where the
isocyanate was a liquid, it was added neat on small scale
reactions such as this. However, the reaction is exothermic
30. Van Den Pol, A. N.; Gao, X.; Obrietan, K.; Kilduff, T. S.;
Belousov, A. B. J. Neurosci. 1998, 18, 7962.
31. Cheng, Y.-C.; Prusoff, W. H. Biochem. Pharmacol. 1973,
22, 3099.