Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent corticotropin-releasing factor-1 antagonists with adequate lipophilicity and water solubility

Article abstract of DOI:10.1016/j.bmcl.2004.05.019

In our efforts to identify potent CRF₁ antagonists with proper physicochemical properties, a series of 3-phenylpyrazolo[1,5-a]pyrimidines bearing polar groups, such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized. Several positions of the core structure were identified, where a polar group was tolerated with slight reduction in receptor binding. NBI 30545 (18n) was found to have good binding affinity and potent antagonistic activity at the human CRF₁ receptor. Moreover, this compound had proper lipophilicity (logD=2.78) and good solubility in water (>10mg/mL), and exhibited good plasma and brain exposure when given orally.

Full text of DOI:10.1016/j.bmcl.2004.05.019

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3669–3673
Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent
corticotropin-releasing factor-1 antagonists with adequate
lipophilicity and water solubility
Chen Chen,a,* Keith M. Wilcoxen,a Charles Q. Huang,a James R. McCarthy,a
Takung Chenc and Dimitri E. Grigoriadisb
aDepartment of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA
bDepartment of Pharmacology, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA
cDepartment of Preclinical Development, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA
Received 1 April 2004; revised 10 May 2004; accepted 11 May 2004
Abstract—In our efforts to identify potent CRF1 antagonists with proper physicochemical properties, a series of 3-phenylpyraz-
olo[1,5-a]pyrimidines bearing polar groups, such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized. Several
positions of the core structure were identified, where a polar group was tolerated with slight reduction in receptor binding. NBI
30545 (18n) was found to have good binding affinity and potent antagonistic activity at the human CRF1 receptor. Moreover, this
compound had proper lipophilicity (log D ¼ 2:78) and good solubility in water (>10 mg/mL), and exhibited good plasma and brain
exposure when given orally.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
lipophilicity and poor water solubility.6 We calculated
the Clog P values of 1–7 using the ACD/LogP software7
to assess the relative lipophilicities of these molecules.
All of the compounds, except DMP904 (3), have Clog P
values close to or greater than 6,8 much too high as ideal
CNS agents since a preferred log P value should be be-
tween 2 and 3.5.9 Recently, CRF1 receptor antagonists
with lower lipophilicity have been identified.10 For
example, DMP696 (8) is a potent CRF1 antagonist with
good in vitro activity, good pharmacokinetic property
and in vivo efficacy in anxiety animal models. The
Clog P value of 8 is 3.32.11 Here we report the synthesis
and structure–activity relationships of 3-phenylpyraz-
olo[1,5-a]pyrimidines such as NBI 30545 (18n)12 in our
efforts to identify potent CRF1 antagonists with proper
physicochemical properties (Fig. 1).
Corticotropin-releasing factor (CRF), a 41-amino acid
peptide produced in hypothalamus, is a major modula-
tor of the body’s responses to stress. CRF exerts its
function by binding to and activating the CRF1 and
CRF2 receptors, both belonging to the class B G-pro-
tein-coupled receptor superfamily.1 Clinical evidence
suggests that over-stimulation of the CRF system may
result in several diverse neuropsychiatric diseases
including depression, anxiety and stress related disor-
ders, and that CRF antagonists have the potential to
treat these diseases. Since the first nonpeptide CRF
antagonist CP-154,526 (1) disclosed in 1996,2 many
potent small molecule CRF antagonists from different
chemical classes have been reported.3 Among them a
series of 3-phenylpyrazolo[1,5-a]pyrimidines, exempli-
fied by PD171729 (2)4b and DMP904 (3),4c have been
synthesized by several groups.4 Like many other small
molecule CRF1 antagonists reported previously (4–7),5
this series of compounds such as 2 suffer from high
2. Chemistry
The synthesis of the desired 3-phenylpyrazolo[1,5-a]-
pyrimidines 18–20 was started from the substituted
phenylacetonitriles 9 as described in Schemes 1 and 2. b-
Ketonitriles 10 and 11 were prepared by reaction of 9
with sodium hydride in THF, followed by a carboxylic
Keywords: Pyrazolopyrimidine; CRF; Antagonist.
* Corresponding author. Tel.: +1-858-658-7600; fax: +1-858-658-7619;
e-mail: cchen@neurocrine.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.019

3670
C. Chen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3669–3673
Cl
N
N
N
Cl
Cl
H
N
N
N
NH
N
N
N
N
N
N
N
N
N
N
N
Cl
Cl
Cl
O
Antalarmin (5)
DMP904 (3)
NBI 27914 (4)
CP-124,526 (1)
PD171729 (2)
O
O
O
S
2
1
N
N
S
F
O
N
Cl
N
NH
7
3
N
N
N
N
N
N
6
N
O
Cl
N
N
4N
O
5
Cl
F
NBI 30545 (18n)
SSR125543A (7)
DMP696 (8)
CRA1000 (6)
Figure 1. Some small molecule CRF1 receptor antagonists.
1
1
O
R
R
N
N
NH
OH
N
N
d
N
a
b
c
e
CN
N
NH
2
X
X
2
X
X
R
10
9
1
2
1
THP
O
14a: R = Me, R = Me
13a: R = Me
O
1
2
1
14b: R = Me, R = Et
13b: R = SMe
CN
1
2
1
14c: R = Me, R = CF
13c: R = CH OTHP
3
2
Cl
Cl
1
2
Cl
14d: R = Me, R = CH OMe
2
9a
11
1
1
2
15:
16:
R
R
= SMe, R = Me
2
S
S
= CH OTHP, R = Me
2
CN
CN
Cl
Cl
Cl
9b
12
Scheme 1. Reagents and conditions: (a) NaH/THF, then AcOEt; (b) NaH/THF, then THPOCH2COOEt; (c) i. NaH/THF/rt, ii. CS2, iii. MeI;
(d) NH2NH2ÆHCl/aq EtOH/reflux; (e) R2COCH2COOEt/dioxane/reflux.
R3
N
R3
N
R1
R1
N
N
4
N
4
Cl
R
R
N
N
N
b
a
or
14,15
N
N
N
R2
R2
X
X
X
19a: R2 = Et
18: R1 = Me
20: R1 = SMe
17
19b: R2 = CF3
19c: R2 = CH2OMe
Scheme 2. Reagents and conditions: (a) POCl3/reflux; (b) R3R4NH/reflux.
ester.4c Compound 12 was prepared as a yellowish solid
by reaction of 9b with 2.5 equiv of sodium hydride in
THF, followed by excess amount of carbon disulfide
and then methyl iodide. The 3-phenylpyrazolo[1,5-a]-
pyrimidinones 14–16 were synthesized using a procedure
similar to that reported.13 In brief, 10–12 were cyclized
with hydrazine hydrochloride in refluxing aqueous eth-
anol to give the aminopyrazoles 13, which were sub-
jected to a second cyclization with a b-ketoester in
refluxing dioxane to give the pyrazolo[1,5-a]pyrimidi-
nones 14–16 as white solids. Compounds 14 and 15 were
converted to the corresponding chloropyrimidines 17
with POCl3 at reflux, which were subsequently reacted
with an alkylamine to afford the desired products 18–20.
further purification, was treated with dimethylamine in
acetonitrile first at room temperature, followed by ex-
cess dipropylamine at reflux to provide a mixture of the
2-hydroxylmethyl 22 and the 2-(dimethylamine)methyl
23 that were separated by chromatography (Scheme 3).
Hydrolysis of the 4-cyanophenyl analog 18b under
acidic conditions (6 N HCl/EtOH, reflux) gave the cor-
responding carboxylic acid 24. On the other hand,
reduction of 18b with boran/THF gave the 4-amino-
methylphenyl analog 25 (Scheme 4).
Demethylation of 18e with BCl3 in dichloromethane at
0 °C to rt gave the phenol 26, which was alkylated with
2-dimethylaminoethyl chloride under basic conditions
(K2CO3/EtOH) to give the amine 27 (Scheme 5). Oxi-
dation of the methylsulfide 20 with 1.5 equiv of m-CPBA
in dichloromethane at 0 °C afforded the corresponding
Reaction of 16 with POCl3 at reflux gave the interme-
diate 21, which, after aqueous workup and without

C. Chen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3669–3673
OH N
3671
Cl
N
N
N
Cl
N
N
N
N
N
b
a
+
16
N
N
N
Cl
Cl
Cl
21
23
22
Scheme 3. Reagents and conditions: (a) POCl3/reflux; (b) Me2NH/ACN/rt, then Pr2NH/reflux.
N
N
N
N
N
N
N
N
b
N
a
N
N
N
H N
2
HOOC
NC
18b
24
25
Scheme 4. Reagents and conditions: (a) 6 N HCl/EtOH/reflux; (b) BH3/THF.
N
N
N
N
N
N
b
N
N
N
a
N
N
N
N
O
MeO
HO
18e
26
27
Scheme 5. Reagents and conditions: (a) BCl3/CH2Cl2, 0 °c to rt; (b) Me2NCH2CH2ClÆHCl/K2CO3/EtOH/n.
O
S
O O
S
S
N
N
N
N
N
N
N
N
N
a
+
N
N
N
Cl
Cl
29
Cl
Cl
Cl
20
Cl
28
Scheme 6. Reagents and conditions: (a) m-CPBA/CH2Cl2/rt.
sulfoxide 28 and sulfone 29, which were separated by
chromatography on silica gel (Scheme 6).
Although compound 2 exhibits very good binding
affinity (Ki ¼ 1:3 nM in our assay, 3.2 nM, reported)4b at
the human CRF1 receptor, it is highly lipophilic with a
Clog P value of 5.86. Moreover, its mesylate salt is lar-
gely insoluble in water. In order to reduce its lipophi-
licity, we introduced polar groups such as a hydroxyl,
methoxy, sulfoxide and weakly basic amino group into a
different position of this core structure. The 2-, 3- and 4-
methoxyphenyl compounds 18d, 18e and 18f had Clog P
values of about 4.7, and among them the 4-methoxy
analog 18f possessed the best binding affinity
(Ki ¼ 3:6 nM). Incorporation of an additional methoxy
group into 18f further lowered the lipophilicity and
slightly increased binding affinity. Thus, the 3,4-di-
methoxyphenyl compound 18h had a Ki of 1.3 nM and
Clog P of 4.45. Similarly, the 2,4-dimethoxyphenyl
analog 18i possessed a Ki value of 1.1 nM and Clog P of
4.33. Optimization at the 7-position of the pyrazolo-
pyrimidine with different alkylamines resulted in several
compounds with good binding affinity as well as proper
lipophilicity. For example, 18l and 18n possessed Ki
values of 2.4 and 3.4 nM, and Clog P values of 4.16
and 3.18, respectively. The binding affinities of these
3. Results and discussion
The synthesized compounds were tested for their bind-
ing affinities at the cloned human CRF1 receptor in a
competition binding assay as described,14 and the Ki
values were determined from concentration–response
curves using concentrations ranging from 100 pM to
10 lM. The structure–activity relationships of these
compounds are summarized in Table 1. Selected com-
pounds were also evaluated for functional antagonism
in the same cell line as that used in the binding studies
above however utilizing a live whole cell preparation to
measure intracellular cAMP accumulation, and further
determined in an assay based on their ability to inhibit
CRF-stimulated ACTH release in cultured rat anterior
pituitary cells.15 These results are summarized in Table
2. Antalarmin (5), which is utilized as a positive control,
displayed a Ki of 2.6 nM in the binding assay and an
IC50 of 16 nM in the cAMP inhibitory assay.

3672
C. Chen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3669–3673
Table 1. SAR and Clog P of substituted 3-phenylpyrazolo[1,5-a]pyrimidines17
3
1
R
R
N
N
4
N
R
N
2
X
R
Compound
X
R1
R2
––
R3NR4
Ki (nM)a
Clog Pb
5
––
2,4-Cl
––
––
2.6
1.3
8.89
5.86
5.54
4.28
4.97
4.63
4.73
4.78
4.49
4.45
4.33
3.89
4.33
4.16
2.51
3.18
2.03
6.07
6.80
4.82
6.09
3.93
4.84
4.74
3.84
4.63
3.73
3.68
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CH2OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
PrNCH2Pr-c
Pr2N
Pr2N
18a
18b
18c
18d
18e
18f
18g
18h
18i
18j
18k
18l
18m
18n
18o
19a
19b
19c
20
4-Cl
4-CN
1.6
3.5
H
Pr2N
Pr2N
69
15
2-MeO
3-MeO
4-MeO
4-MeO
3,4-MeO
2,4-MeO
2,4-MeO
2,4-MeO
2,4-MeO
2,4-MeO
2,4-MeO
2,4-MeO
4-Cl
Pr2N
Pr2N
24
3.6
PrNCH2Pr-c
Pr2N
Pr2N
2.4
1.3
1.1
3.9
Et2CHNH
EtNBu-n
PrNHCH2Pr-c
PrNCH2CH2OH
PrNCH2CH2OMe
(MeOCH2CH2)2N
Pr2N
1.9
2.4
29
3.4
43
100
4-Cl
4-Cl
CF3
Pr2N
Pr2N
>10,000
>10,000
0.73
11
CH2OMe
SMe
Me
2,4-Cl
4-Cl
4-Cl
PrNCH2Pr-c
Pr2N
Pr2N
22
23
CH2NMe2
Me
Me
Me
Me
>10,000
>10,000
>10,000
>10,000
8.6
24
25
4-COOH
4-CH2NH2
4-OCH2CH2NMe2
2,4-Cl
Pr2N
Pr2N
Me
Me
27
28
Me
Me
Pr2N
PrNCH2Pr-c
PrNCH2Pr-c
SOMe
SO2Me
29
2,4-Cl
Me
150
a Values are average of two or more independent determinations.
b ACD/LogP software.
Table 2. Inhibition of CRF-stimulated cAMP production and ACTH
release
from 18a. The sulfoxide 28 had a Ki value of 8.6 nM,
about 12-fold lower than the methylthio analog 20
(Ki ¼ 0:73 nM). The calculated log P values of 22 (3.93)
and 28 (3.73) were, however, much lower than 18a and
20. The bulky sulfone group at the 2-position of pyr-
azolo[1,5-a]pyrimidine caused a large reduction in
binding affinity (29, Ki ¼ 150 nM). The weakly basic
dimethylamino moiety at the 2-methyl group of 18a
completely abolished its binding (23, Ki > 10 lM). These
data may suggest this position is more sensitive to
bulkiness than a polar group.
Compound
Ki (nM)
cAMP IC50 (nM) ACTH IC50 (nM)
5
2.6
1.3
1.6
1.1
3.9
3.4
11
16.3
33
––
––
2
18a
18i
18j
18n
22
28
38
34
118
106
––
38
76
37
470
210
––
––
8.6
compounds are comparable to 2, however, their lipo-
philicities are much lower than 2 (Clog P ¼ 5:86).
Because of the success in incorporation of the hydro-
philic methoxyl moiety at the 3-phenyl group, we further
explored several other alternatives. Both the acidic car-
boxylate (24) and basic amine (25) substitutions at the
para-position of the 3-phenyl group gave inactive ana-
logs. Attempts to distance the basic moiety from the
core structure were also unsuccessful (27, Ki > 10 lM).
Attempts to incorporate a methoxy group at the 5-po-
sition of the core were unsuccessful. Thus, 19c was
inactive (Ki > 10 lM). This could simply be due to a
stereo-effect since the 5-ethyl analog 19a (Ki ¼ 100 nM)
had a much higher binding Ki than the corresponding
5-methyl compound 18a (Ki ¼ 1:6 nM). The CF3-analog
19b also exhibited no binding (Ki > 10 lM).
These results suggest that, for this series of compounds,
introduction of a polar methoxy group at 7-position side
chain had little change in receptor binding. For example,
18i and its oxygen-inserted analog 18n had Ki values of
1.1 and 3.4 nM, respectively. However, the additional
oxygen of 18n decreased the lipophilicity (log P) about
one log unit. The 5-position did not tolerate the meth-
The 2-position of the core structure seemed to be less
sensitive to a polar substituent. Thus, the 2-hydroxy-
methylpyrazolo[1,5-a]pyrimidine 22 exhibited a Ki value
of 11 nM, about sevenfold reduction in binding affinity

C. Chen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3669–3673
3673
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III; Winston, E. N.; Chen, Y. L.; Heym, J. PNAS 1996, 93,
10477.
oxy moiety and a group larger than the methyl. The 3-
phenyl group was open to multiple methoxy substitu-
ents, but did not tolerate acidic and basic functionalities
at the para-position. Introducing a polar moiety at the 2-
position was somewhat successful. The 2-hydroxymethyl
(22) and 2-sulfoxide (28) analogs possessed acceptable
binding affinities and proper lipophilicities.
3. For a recent review, see: Grigoriadis, D. E.; Haddach, M.;
Ling, N.; Saunders, J. Curr. Med. Chem. 2001, 1,
63.
4. (a) Chen, C.; Webb, T. R.; McCarthy, J. R.; Moran, T. J.;
Wilcoxen, K. M. WO 9,729,109, 1997; (b) Wustrow, D. J.;
Capiris, T.; Rubin, R.; Knobelsdorf, J. A.; Akunne, H.;
Davis, M. D.; MacKenzie, R.; Pugsley, T. A.; Zoski, K.
T.; Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett.
1998, 8, 2067; (c) Gilligan, P. J.; Baldauf, C.; Cocuzza, A.;
Chidester, D.; Zaczek, R.; Fitzgerald, L. W.; McElroy, J.;
Smith, M. A.; Shen, H. L.; Saye, J. A.; Christ, D.; Trainor,
G.; Robertson, D. W.; Hartig, P. Bioorg. Med. Chem.
2000, 8, 181.
5. (a) Chen, C.; Dagnino, R., Jr.; De Souza, E. B.; Grigor-
iadis, D. E.; Huang, C. Q.; Kim, K. I.; Liu, Z.; Moran, T.;
Webb, T. R.; Whitten, J. P.; Xie, Y. F.; McCarthy, J. R. J.
Med. Chem. 1996, 39, 4358; (b) Webster, E. L.; Lewis, D.
B.; Torpy, D. J.; Zachman, E. K.; Rice, K. C.; Chrousos,
G. P. Endocrinology 1996, 137, 5747; (c) Arai, K.; Ohata,
H.; Shibasaki, T. Neurosci. Lett. 1998, 255, 103; (d)
Griebel, G.; Simiand, J.; Steinberg, R.; Jung, M.; Gully,
D.; Roger, P.; Geslin, M.; Scatton, B.; Maffrand, J.-P.;
Soubrie, P. J. Pharmacol. Exp. Ther. 2002, 301,
333.
6. Hsin, L.-W.; Tian, X.; Webster, E. L.; Coop, A.; Caldwell,
T. M.; Jacobson, A. E.; Chrousos, G. P.; Gold, P. W.;
Habib, K. E.; Ayala, A.; Eckelman, W. C.; Contoreggi, C.;
Rice, K. C. Bioorg. Med. Chem. 2002, 10, 175.
7. Advanced Chemistry Development, Inc., 90 Adelaide
Street West, Toronto, ON M5H 3V9, Canada.
8. Clog P values are 8.43 for 1, 5.86 for 2, 4.80 for 3, 9.71 for
4, 8.89 for 5, 5.98 for 6 and 7.75 for 7.
9. Waterhouse, R. N. Mol. Imaging Biol. 2003, 5, 376.
10. (a) Li, Y.; Hill, G.; Wong, H.; Kelly, N.; Ward, K.;
Pierdomenico, M.; Ren, S.; Gilligan, P.; Grossman, S.;
Trainor, G.; Taub, R.; McElroy, J.; Zazcek, R. J.
Pharmacol. Exp. Ther. 2003, 305, 86; (b) Chaki, S.;
Nakazato, A.; Kennis, L.; Nakamura, M.; Mackie, C.;
Sugiura, M.; Vinken, P.; Ashton, D.; Langlois, X.;
Steckler, T. Eur. J. Pharmacol. 2004, 485, 145.
11. He, L.; Gilligan, P. J.; Zaczek, R.; Fitzgerald, L. W.;
McElroy, J.; Shen, H.-S. L.; Saye, J. A.; Kalin, N. H.;
Shelton, S.; Christ, D.; Trainor, G.; Hartig, P. J. Med.
Chem. 2000, 43, 449.
Compounds of interest were selected for measurement
of their antagonistic activities in functional assays
including inhibition of CRF-stimulated cAMP produc-
tion in cells expressing the human CRF1 receptor, and
CRF-stimulated ACTH release in rat anterior pituitary
primary cell cultures (Table 2). All compounds tested
exhibited functional antagonism in both assays. For
example, 28 exhibited an IC50 value of 210 nM in the
cAMP assay, and 18n had IC50 values of 76 nM in the
cAMP assay and 37 nM in the ACTH assay.
The experimentally measured log P value of 18n was
2.78 (octanol–PBS buffer, pH 7.4, HPLC detection),
which approximately matches the calculated value
(3.18). In contrast with 2, which is quite insoluble in
water, the mesylate salt of 18n had very good water
solubility (>10 mg/mL). Compound 18n also had a good
pharmacokinetic profile in rats. After intravenous
injection to Sprague–Dawley rats (10 mg/kg), the vol-
ume of distribution was calculated to be 4.7 L/kg, indi-
cating extensive tissue distribution. The clearance of
43 mL/min kg for this compound was high in this spe-
cies, and this resulted in a relatively short half-life of
1.1 h. At the dose of 10 mg/kg po, the plasma and brain
AUC values were 1182 ng/ml h and 1472 ng/g h, respec-
tively. This resulted in an oral bioavailability of 30.5%
and a brain/plasma ratio of 1.2. These data indicate 18n
had good plasma and brain exposure when adminis-
trated orally. In comparison, the high lipophilic CP-
124,526 (1, Clog P ¼ 8:43) has a long half-life (51 h)
associated with high volume of distribution (105 L/kg) in
rats.16
4. Conclusion
12. Part of this work has been presented in 217th ACS
National Meeting, Anaheim: Wilcoxen, K.; Chen, C.;
Huang, C.; Haddach, M.; Xie, Y.; Wing, L.; Grigoriadis,
D. E.; De Souza E. B.; McCarthy, J. R. 217th ACS
National Meeting, Anaheim, CA, Mar 21–25, 1999; Book
of Abstract: MEDI 002.
13. (a) Novinson, T.; Bhooshan, B.; Okabe, T.; Revankar,
G. R.; Robins, R. K.; Senga, K.; Wilson, H. R.
J. Med. Chem. 1976, 19, 512; (b) Senga, K.; Novinson,
T.; Wilson, H. R.; Robins, R. K. J. Med. Chem. 1981, 24,
610.
SAR studies at the 2-, 3-, 5- and 7-positions of the 3-
phenylpyrazolo[1,5-a]pyrimidine towards more hydro-
philic derivatives revealed that the 5-position was very
sensitive to any replacement of the optimal methyl
group. However, the 2-, 3- and 7-positions were some-
what tolerated to a small hydrophilic group, with a
slight reduction in binding affinity. Several compounds
such as 18n were identified with good binding affinity,
potent functional antagonistic activity and suitable
lipophilicity for a CNS agent. Compound 18n also
possessed good plasma and brain exposure after oral
administration.
14. Grigoriadis, D. E.; Liu, X. J.; Vaughn, J.; Palmer, S. F.;
True, C. D.; Vale, W. W.; Ling, N.; De Souza, E. B. Mol.
Pharmacol. 1996, 50, 679.
15. Battaglia, G.; Webster, E. L.; De Souza, E. B. Synapse
1987, 1, 572.
References and notes
16. Keller, C.; Bruelisauer, A.; Lemaire, M.; Enz, A. Drug
Metab. Dispos. 2002, 30, 173.
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2. Schulz, D. W.; Mansbach, R. S.; Sprouse, J.; Braselton, J.
P.; Collins, J.; Corman, M.; Dunaiskis, A.; Faraci, S.;
17. For most compounds assayed 2–5 times, the Ki values
were highly reproducible with an average standard devi-
ation of <50%.