Discovery of PF-00217830: Aryl piperazine napthyridinones as D2 partial agonists for schizophrenia and bipolar disorder

Article abstract of DOI:10.1016/j.bmcl.2011.01.059

The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D₂ partial agonists is described. Our goal was to optimize the affinities for the D₂, 5-HT_2A and 5-HT_1A receptors, such that the D₂/5-HT_2A ratio was greater than 5 to ensure maximal occupancy of these receptors when the D₂ occupancy reached efficacious levels. This strategy led to identification of PF-00217830 (2) with robust inhibition of sLMA (MED = 0.3 mg/kg) and DOI-induced head twitches in rats (31% and 78% at 0.3 and 1 mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg).

Full text of DOI:10.1016/j.bmcl.2011.01.059

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2621–2625
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of PF-00217830: Aryl piperazine napthyridinones as D2 partial
agonists for schizophrenia and bipolar disorder
Douglas S. Johnson a,b, , Chung Choi b, Lorraine K. Fay b, David A. Favor b, Joseph T. Repine b,
⇑
Andrew D. White b, Hyacinth C. Akunne b, Lawrence Fitzgerald a,b, Kim Nicholls b,
Bradley J. Snyder a,b, Steven Z. Whetzel b, Liming Zhang a,b, Kevin A. Serpa a,b
a Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA
b Pfizer Worldwide Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and structure–activity relationship (SAR) of a novel series of aryl piperazine napthyridi-
none D2 partial agonists is described. Our goal was to optimize the affinities for the D2, 5-HT2A and 5-
HT1A receptors, such that the D2/5-HT2A ratio was greater than 5 to ensure maximal occupancy of these
receptors when the D2 occupancy reached efficacious levels. This strategy led to identification of PF-
00217830 (2) with robust inhibition of sLMA (MED = 0.3 mg/kg) and DOI-induced head twitches in rats
(31% and 78% at 0.3 and 1 mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg).
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 December 2010
Revised 13 January 2011
Accepted 14 January 2011
Available online 22 January 2011
Keywords:
D2 partial agonist
Napthyridinone
PF-00217830
Schizophrenia
Schizophrenia is a mental disorder that is characterized by po-
sitive symptoms such as delusions, hallucinations and disorga-
nized speech/behavior and negative symptoms including apathy,
withdrawal, lack of pleasure and impaired attention. The atypical
antipsychotics (risperidone, olanzapine, quetiapine and ziprasi-
done) are all D2 antagonists with relatively more potent blockade
of 5-HT2A receptors and they also possess a range of activities at
other receptors.1,2 Aripiprazole (1) was approved by the US Food
and Drug Administration in 2002 as the first D2 partial agonist
for use in the treatment of psychiatric disorders.3,4 It can act as
an agonist on pre-synaptic autoreceptors, which have a high recep-
tor reserve, and as an antagonist on D2 post-synaptic receptors,
where significant levels of endogenous dopamine exist and there
is no receptor reserve.5,6 Clinical studies have demonstrated that
aripiprazole is well tolerated and does not significantly induce
extrapyramidal side effects (EPS), weight gain, sedation, QT prolon-
gation, prolactin elevation or tardive dyskinesia.7,8 Atypical anti-
psychotics that are D2 antagonists tend to cause EPS when the D2
occupancy is above 80%.9,10 In contrast, EPS was rarely observed
with aripiprazole at clinically effective doses where approximately
90% of striatal D2 receptors were occupied.11–13 One hypothesis is
that the partial agonist activity of aripiprazole (intrinsic activity
(IA) of approximately 30%)5 prevents the functional D2 blockade
from rising above 70%, which is above the 65% D2 occupancy
needed for a clinical response but below the 80% D2 occupancy
where EPS is observed.10,14,15 Aripiprazole is also an antagonist at
5-HT2A receptors and a partial agonist at 5-HT1A receptors,16 which
may confer additional protection against the induction of EPS, as
well as providing additional efficacy;17 however the 5-HT2 and 5-
HT1A receptor occupancy is considerably lower than that for the
D2 receptor.12
Cl
N
Cl
N
O
N
H
O
Aripiprazole (1)
N
N
O
N
N
O
H
PF-00217830 (2)
This Letter presents the discovery of PF-00217830 (2), a D2 par-
tial agonist (D2PA) which advanced to phase 2 clinical studies as a
treatment for schizophrenia.18 Our target pharmacological profile
was dopamine D2 partial agonism (IA of 30–50%),19 serotonin
5-HT1A partial agonism (IA of 60–90%),20 and serotonin 5-HT2A
⇑
Corresponding author.
E-mail address: doug.johnson@pfizer.com (D.S. Johnson).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.059

2622
D. S. Johnson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2621–2625
antagonism.21 We targeted a higher affinity at 5-HT2A and 5-HT1A
to ensure maximal occupancy of these receptors when efficacious
levels of D2 occupancy were achieved. In vivo intrinsic activity
presence of HF in pyridine gave fluoronapthyridinone 9 in excel-
lent yield. Addition of 4-(benzyloxy)butan-1-ol to 9 using potas-
sium tert-butoxide as base afforded 10. The yield was improved
by adding a catalytic amount of Bu4NBr. Hydrogenation of 10 re-
sulted in reduction to the dihydronaphthyridinone with concomi-
tant removal of the benzyl group to give 13. Oxidation of 13 with
IBX followed by reductive amination of aldehyde 14a with aryl
piperazines provided the desired aryl piperazine dihydronaphthy-
ridinones 15a.
Alternatively, fluoronapthyridinone 9 was reacted with dry 1,4-
butanediol and sodium hydride in NMP to give 12 directly or 9 was
reacted with 4-(tetrahydro-2H-pyran-2-yloxy)butan-1-ol to give
11 followed by removal of the THP protecting group under mild
conditions. Alcohol 12 was oxidized to aldehyde 14b and subjected
to various aryl piperazines under reductive amination conditions
to give the aryl piperazine naphthyridinones 15b in a similar man-
ner as that described for the transformation of 13 to 15a. Analogs
with [1,6]-naphthyridinone and pyrido[2,3-d]pyrimidin-7(8H)-one
B-rings were prepared in an analogous fashion.25
We next investigated the effect of substituents at the 2- and 3-
position of the phenyl A-ring (Table 2). Substituents at both the 2-
and 3-position of the phenyl ring were generally required for good
5-HT2A activity. Replacing either of the chloro substituents of 4
with a methyl group led to compounds with improved 5-HT2A
activity and higher D2/5-HT2A ratios (18 and 21). The 2,3-dimethyl-
phenylpiperazine compound 20 had a D2/5-HT2A ratio of 7, which
was the highest of the substituted phenyl analogs that were eval-
uated. Analogs with only one substituent (i.e., 16 and 19) or with a
smaller fluoro substituent (i.e., 17 and 22) had significantly inferior
D2/5-HT2A ratios. A trifluoromethyl group was tolerated at the 2-
position (24), but at the 3-position led to a lower D2/5-HT2A ratio
and D2 IA (23). Nearly all the analogs had D2 intrinsic activities
in the desired range (IA = 27–38%).
The potent D2 and 5-HT2A activity as well as the higher D2/5-HT2A
ratio for the 2,3-dimethyl compound 20 led to the investigation
of related bicyclic A rings (Table 3). The indane and tetrahydro-
naphthalene analogs 25 and 26 had excellent D2/5-HT2A ratios
but the D2 IA fell below our desired partial agonism range. Incorpo-
rating oxygen’s in the benzylic positions of 26 resulted in similar
D2 and 5-HT2A potency and D2 IA, but the 5-HT1A affinity im-
proved.26 Lastly we incorporated a naphthyl piperazine A-ring to
give 2. Compound 2 had subnanomolar affinity for the D2 and
(IA) was determined by blockade of the c-butyrolactone (GBL)-in-
duced increase in DOPA synthesis in mice.22 Inhibition of sponta-
neous locomotor activity (sLMA) was used to evaluate
compounds for efficacy against the positive symptoms of schizo-
phrenia23 and induction of catalepsy was used to benchmark the
liability for EPS.24 Changing the quinolinone core to a [1,8]-nap-
thpyridinone ultimately resulted in the discovery of PF-00217830
(2), a compound that maintains a similar degree of D2 partial agon-
ism, but is a more potent antagonist and partial agonist at the 5-
HT2A and 5-HT1A receptors, respectively. PF-00217830 was more
potent than aripiprazole (1) in preclinical models predictive of
antipsychotic activity (sLMA), whilst not inducing catalepsy at
30Â the sLMA minimally effective dose (MED) suggesting the com-
pound has a low likelihood of inducing EPS.
Our initial design focus was to investigate the effect of incorpo-
rating nitrogens in the B-ring while retaining the A-ring as dichlo-
ropiperazine (Table 1). Initially we made the carbon linked [1,8]-
napthpyridinone 3. We were encouraged that this compound had
comparable D2 affinity and IA as aripiprazole (1) with improved
5-HT2A affinity. Unfortunately, 3 had very low oral bioavailability
(%F = 6 in rat). We next made the oxygen linked version (4) and
it had nearly the same activity at D2, 5-HT2A and 5-HT1A as 3 with
improved oral bioavailability (%F = 23 in rat). The corresponding
dehydro-[1,8]-napthpyridinone analog 5 had a similar D2 affinity
as 4, but the 5-HT2A activity was diminished. We also investigated
the activity of the [1,6]-napthpyridinone and the pyrido[2,3-d]pyr-
imidin-7(8H)-one B-rings (6 and 7). Analogs 6 and 7 had nearly the
same D2 receptor affinity, but had reduced affinity for 5-HT2A and
5-HT1A receptors compared to the corresponding [1,8]-napthpyrid-
inone analog 4. In addition, the D2 IA of 6 and 7 (19% and 28%,
respectively) was a little lower than what we were targeting.
Therefore, based on the improved 5-HT2A and 5-HT1A activity and
the higher D2/5-HT2A ratio of 4 compared to aripiprazole, we chose
to further explore the SAR of the oxygen-linked [1,8]-napthpyridi-
none series.
The general synthesis for the aryl piperazine [1,8]-napthyridi-
nones (15) is shown in Scheme 1.25 Treatment of 2,6-diaminopyr-
idine with
D,L-malic acid in concentrated H2SO4 provided
aminonapthyridinone 8 in good yield. Diazotization of 8 in the
Table 1
SAR of B-rings
Cl
Cl
N
N
Cl
N
N
N
X
N
H
O
O
3
Y
Cl
O
N
H
A-ring
4-7
B-ring
Compd
X
Y
bond
D2(Ki, nM)
5-HT2A (Ki, nM)
5-HT1A (Ki, nM)
D2%IA(TU)
1
3
4
5
6
7
CH
CH
Single
1.8
2.6
1.0
1.0
2.0
1.0
9.6
10.3
11.4
17.7
14.0
40.7
52.7
37
34
30
19
19
28
0.79
0.13
1.6
2.9
3.2
N
N
CH
N
CH
CH
N
Single
Double
Double
Double
N

D. S. Johnson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2621–2625
2623
a
b
H2SO4
H2N
N
N
H
O
H2N
N
NH2
8
c or d
or e
g
RO
O
N
h
N
H
F
N
N
H
O
O
R = Bn (10)
R = THP (11)
R = OH (12)
9
f
h
HO
O
O
N
N
O
O
N
N
H
O
H
13
14a: saturated
14b: unsaturated
Ar
Ar
N
N
NH
N
O
N
N
H
O
i
15a: saturated
15b: unsaturated
Scheme 1. Reagents and conditions: (a) D,L
-malic acid, H2SO4, 85%; (b) NaNO2, HF-pyridine, 90%; (c) BnO(CH2)4OH, KOtBu, Bu4NBr, THF, 90%; (d) HO(CH2)4OH, NaH, NMP,
68 °C, 62%; (e) THPO(CH2)4OH, KOtBu, NMP, 120 °C, 1 h, 89%; (f) HCl in dioxane, MeOH, 1 h, 94%; (g) H2, Pd/C, MeOH, 95%; (h) IBX, EtOAc, 80 °C, 79–95%; (i) NaBH(OAc)3, DCE,
50-80%.
Table 2
SAR of 2,3-substituted A-rings
R2
N
R1
N
O
N
N
H
O
Compd
R1
R2
D2 (Ki, nM)
5-HT2A (Ki, nM)
5-HT1A (Ki, nM)
D2%IA (TU)
16
17
18
19
20
21
22
23
24
Cl
Cl
Cl
Me
Me
Me
F
Cl
CF3
H
F
Me
H
Me
Cl
Cl
CF3
Cl
5.7
2.5
1.0
5.0
2.5
3.0
1.0
1.0
3.0
15.9
31.2
0.50
50.9
0.35
1.5
10.4
12.0
1.4
4.6
1.7
13.8
3.9
8.5
8.4
1.2
0.95
3.5
31
29
29
38
28
35
31
15
33
5-HT2A receptors and a D2/5-HT2A ratio of 6. In addition, the affinity
at the 5-HT1A receptor was improved compared to aripiprazole and
the in vitro 5-HT1A IA was 70–80% in a thymidine uptake functional
assay, compared to an IA of 64% for aripiprazole. The D2 intrinsic
activity of 2 was similar to aripiprazole (1).
We next investigated the effects of fluorine substitution on the
napthyl A-ring of 2 (Table 4).27 Subtle changes with respect to the
position of the fluorine substituent had large effects on the D2
intrinsic activity, leading to compounds that range from antago-
nism (i.e. 29) to higher intrinsic activity partial agonism (i.e., 35).
Incorporation of a fluorine at the 2-6 positions afforded com-
pounds 29–33 with inferior profiles compared to 2. They all had
D2/5-HT2A ratios of <2 and D2 intrinsic activities more in the range
of an antagonist (IA = 3–19%). However, addition of a fluorine sub-
stituent at the 7- or 8-position of the naphthyl ring afforded
compounds 34 and 35 with good D2 affinity and IA, and excellent
5-HT2A and 5-HT1A potency. In addition, compound 34 had a D2/
5-HT2A ratio >4. Notably, incorporation of a fluorine at the 8-posi-
tion afforded a compound (35) with significantly higher D2 IA com-
pared with aripiprazole (51% vs 36%). Therefore, compounds 2 and
34 met our target profile for a D2 partial agonist similar to 1 with
enhanced serotonergic pharmacology and the in vivo characteriza-
tion of 2 (known as PF-00217830) is discussed below.
The ability of PF-00217830 (2) to block the GBL-induced in-
crease in DOPA synthesis in the mouse brain was used to measure
in vivo dopamine autoreceptor agonist intrinsic activity.22 The
level of partial agonism is determined by the degree of maximum
reversal of the GBL effect reflecting the IA of the compound
(Table 5).28 The in vivo intrinsic activity of 2 (GBL) was a little high-
er than the in vitro intrinsic activity (D2 TU), but 2 was still

2624
D. S. Johnson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2621–2625
Table 3
Table 5
SAR of bicyclic A-rings
In vivo pharmacology summary for aripiprazole (1), PF-00217830 (2) and its active
metabolite 36
A
N
Assay
1
2
36
N
% Blockade of GBL (po)
sLMA (MED, mg/kg, po)
43%
3.0
38%
30
46%
0.3
78%
>10
>30
45%(sc)
1.0
ND
>30
>30
O
N
N
H
O
DOI-induced head twitcha (% inhibition)
Catalepsyb (MED, mg/kg, po)
Ratio of catalepsy MED to sLMA MED
A =
10
O
O
a
25
26
27
28
2
% Inhibition of DOI-induced head twitches in rats @ 3Â sLMA MED.
b
Measure of EPS liability.
Compd
D2 (Ki, nM)
5-HT2A (Ki, nM)
5-HT1A (Ki, nM)
D2%IA (TU)
25
26
27
28
2
1.0
1.4
1.0
0.71
0.81
0.16
0.09
1.3
0.19
0.14
6.3
28
0.78
1.1
3.7
18
21
18
14
38
N
N
O
N
N
H
O
36
determined to be a partial agonist in our desired range (IA of 30–
50%). The in vivo D2 receptor antagonist activity was initially as-
sessed in the sLMA behavioral model, which is predictive of human
antipsychotic efficacy. sLMA behavior is driven, at least in part, by
endogenous dopaminergic tone.23 Compound 2 inhibited sLMA in
rats in a dose-dependent manner with a minimum effective dose
(MED) of 0.3 mg/kg po (Table 5). Preclinical measurement of cata-
lepsy, an akinetic state resulting from the blockade of dopaminer-
The pharmacokinetic profile of PF-00217830 (2) was examined
in rat and monkey (Table 6).33 Following iv administration of 2,
mean plasma clearance values were 14.9 and 5.8 mL/min/kg in
rat and monkey, respectively, indicating low to moderate clearance
in these species. The mean volume of distribution at steady state
(Vdss) values for rat (1.13 L/kg) and monkey (2.62 L/kg) were great-
er than total body water (approximately 0.6–0.7 L/kg), indicating
that 2 distributes to tissues. The mean absolute oral bioavailability
in rats and monkeys was 19.2% and 20.5%, respectively. In toxicol-
ogy studies with rats and monkeys, Cmax and AUC values for 2 in-
creased in a dose-related manner over the dose range evaluated.
PF-00217830 (2) was highly protein bound in plasma with an un-
bound fraction of 1.79%, 0.14%, 0.62% and 0.34% in mouse, rat,
monkey, and human plasma, respectively. PF-00217830 (2) is not
a P-gp substrate and crosses the blood-brain barrier in rats (B/P
AUC(0–7h) ratio = 0.7).
gic neurotransmission, is
a useful model for predicting the
propensity of antipsychotics to produce EPS.29 When tested at
10 mg/kg, po which is 33Â the MED in sLMA, 2 did not show a cat-
aleptic response. In rat ex vivo D2 receptor occupancy studies using
inhibition of [3H]raclopride binding, 2 (10 mg/kg, po) produced
>90% occupancy, further supporting the probability that 2 would
have a low likelihood of inducing EPS.30 In addition, the 5-HT2A
receptor antagonism was assessed in vivo using a DOI-induced
head twitch assay. 5-HT2A behavioral effects were induced by
2,5-dimethoxy-4-iodoamphetamine (DOI), a non-subtype-selec-
tive 5-HT2 agonist, that produces stereotypic head twitches, which
are blocked by selective 5-HT2A receptor antagonists.31 2 reduced
the number of DOI-induced head twitches in rats by 31% and
78%, respectively, at doses of 0.3 and 1 mg/kg po (Table 5). In the
course of these studies, we found that 36 was an active metabolite
of 2. Therefore, 36 was profiled in vitro32 and in vivo and it was
found to have a similar pharmacological profile as 2 (Table 5).
In vitro metabolism of PF-00217830 (2) is consistent across
nonclinical species and humans. All metabolites observed in hu-
man in vitro incubations are present in one or more of the evalu-
ated nonclinical species. In vitro, CYP3A4 and 2D6 play a role in
the metabolism of 2. In vitro studies using pooled human liver
microsomes demonstrated low potential of 2 to inhibit activities
Table 4
SAR of fluoro substituted napthyl A-rings
3
4
2
5
N
N
6
F
8
O
N
N
H
O
7
Compd
F-position
D2 (Ki, nM)
5-HT2A (Ki, nM)
5-HT1A (Ki, nM)
D2%IA (TU)
29
30
31
32
33
34
35
2
3
4
5
6
7
8
1.6
1.1
2.0
6.0
1.0
1.2
1.7
6.7
1.9
11.7
3.3
3.5
0.28
0.67
0.84
3.3
2.0
3.0
1.2
3
14
10
17
19
36
51
1.1
0.77

D. S. Johnson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2621–2625
2625
Table 6
Plasma pharmacokinetic data following administration of PF-00217830 (2) (iv dose of 1 mg/kg and po dose of 3 mg/kg) in male rats and monkeys (n = 3)
Species
Cmax (ng/mL)
tmax (h)
CL (mL/min/kg)
Vdss (L/kg)
iv t1/2 (h)
F (%)
rat
monkey
202
96
1.2
5.0
14.9
5.8
1.1
2.6
6.8
13.6
19.2
20.5
L. A.; Liu, L. X.; Sibley, D. R.; Roth, B. L.; Mailman, R. Neuropsychopharmacology
2003, 28, 1400.
17. (a) Lieberman, J. A.; Mailman, R. B.; Duncan, G.; Sikich, L.; Chakos, M.; Nichols,
D. E.; Kraus, J. E. Biol. Psychiatry 1998, 44, 1099; (b) Roth, B. L.; Hanizavareh, S.
M.; Blum, A. E. Psychopharmacology 2004, 174, 17.
of CYP1A2, 2C9, 2C19, 2D6, and 3A4 based on IC50 values relative to
the predicted efficacious concentration (75.6 ng/mL) in humans.
In summary, PF-00217830 (2) met our laboratory objectives
including an increased affinity for D2, 5-HT2A and 5-HT1A receptors
relative to 1, D2/5-HT2A > 5, D2 IA = 38–46% and 5-HT1A IA = 70–
80%. Furthermore, 2 inhibited sLMA in rats with a minimum effec-
tive dose of 0.3 mg/kg and it reduced the number of DOI-induced
head twitches in rats by 31% and 78% (0.3 and 1 mg/kg, po) with
no catalepsy observed at the highest dose tested (10 mg/kg, po).
18. <http://www.clinicaltrials.gov/ct2/show/NCT00580125?term=PF-
00217830&rank=1/> (last accessed 11-13-2010).
19. Binding assay: [3H]-spiperone binding to a membrane preparation from CHO-
hD2L cells; Functional assay: Intrinsic activity at the dopamine D2 receptor was
assessed using [3H]-thymidine uptake assay using CHO pro-5 cells and were
compared to Quinpirole (full dopamine D2 receptor agonist, 100% IA).
20. Binding assay: Competition binding of test compounds to h5-HT1A receptors
was conducted in membranes prepared from HeLa cells transfected with the
cDNA for h5-HT1A receptors using [3H] 8-OH-DPAT as the receptor agonist. Or,
SPA bead/membrane based assay.
Supplementary data
21. Binding assay: Schmidt, A. W.; Lebel, L. A.; Howard, H. R.; Zorn, S. H. Eur. J.
Pharmacol. 2001, 425, 197.
22. In vivo D2 intrinsic activity (IA) was determined by blockade of the
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.01.059. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
c
-butyrolactone (GBL)-induced increase in DOPA synthesis in mice. Whetzel,
S. Z.; Shih, Y. H.; Georgic, L. M.; Akunne, H. C.; Pugsley, T. A. Neurochem 1997,
69, 2363. In all in vivo studies, the practices and procedures were conducted in
accordance with the NIH Guidelines for Care and Use of Laboratory Animals.
23. Ahlenius, S.; Hillegaart, V. Pharmacol. Biochem. Behav. 1986, 24, 1409.
24. Costall, B.; Naylor, R. J. Arzneim. Forsch 1973, 23, 674; Arnt, J.; Skarsfeldt, T.;
Hyttel, J. Int. Clin. Psychopharmacol 1997, 12, S9.
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T.; Ding, Q.; Maiti, S. N. Tetrahedron Lett. 2007, 48, 5539.
28. Data were normalized to 100% GBL effect and represent mean CI95. Test
compounds were administered po 60 min prior to NSD/GBL, and then
sacrificed 30 min later. Compounds were prepared using 0.5% methocel, 1%
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cremophor and 1% 1N HCl. NSD = 3-hydroxybenzylhydrazine, an
amino acid decarboxylase inhibitor; GBL = -butyrolactone.
L-aromatic
c
29. Catalepsy is measured by placing animals in an unusual posture (grasping a bar
above an elevated surface) and measuring the latency to move from the
abnormal position. Vehicle treated controls spend on the average 7–8 s in this
position. Compounds are judged as producing catalepsy when the majority of
animals spend more than 20 s in the unusual postural position.22
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