Synthesis and binding affinity of potential atypical antipsychotics with the tetrahydroquinazolinone motif

Article abstract of DOI:10.1016/j.bmcl.2009.09.041

A series of 8 new tetrahydroquinazolinone derivatives was synthesized and evaluated for binding affinity to D₂ and 5-HT_2A human receptors; in addition, some properties related to blood-brain barrier penetration were calculated. From

Full text of DOI:10.1016/j.bmcl.2009.09.041

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6059–6062
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and binding affinity of potential atypical antipsychotics
with the tetrahydroquinazolinone motif q
Laura Carro a, Enrique Raviña a, Eduardo Domínguez b, José Brea b, María I. Loza b, Christian F. Masaguer a,
*
a Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela, Spain
b Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2009
Revised 11 September 2009
Accepted 11 September 2009
Available online 17 September 2009
A series of 8 new tetrahydroquinazolinone derivatives was synthesized and evaluated for binding affinity
to D2 and 5-HT2A human receptors; in addition, some properties related to blood–brain barrier penetra-
tion were calculated. From the results of these assays, three compounds were selected for further binding
tests on D1, D3, and 5-HT2C human receptors, which are thought to be involved in schizophrenia. From
these data, compound 19b emerged as the most promising candidate based on its good binding affinities
for D1, D2, and D3 receptors, high affinity for 5-HT2A, low affinity for 5-HT2C receptors, and a Meltzer’s
ratio characteristic of an atypical antipsychotic profile.
Key words:
Tetrahydroquinazolinone
Synthesis
Ó 2009 Elsevier Ltd. All rights reserved.
Binding assays
Dopamine receptors
Serotonin receptors
Antipsychotics
Schizophrenia is a complex psychiatric disorder that affects
approximately 1% of the population.1 The use of classical (typical)
neuroleptics (e.g., haloperidol, Fig. 1) for the treatment of this dis-
ease is associated with severe mechanism-related side effects,
including induction of acute extrapyramidal symptoms (EPS).2 Fur-
thermore, these drugs are ineffective against the negative symp-
toms of schizophrenia. The clinical efficacy of classical
antipsychotics in the treatment of schizophrenia and other psy-
chotic disorders is directly related to their ability to block dopa-
mine D2 receptors in the brain.3 However, it has been reported
that the blockage of the dopamine receptor in the striatum is clo-
sely associated with EPS.4
The introduction of clozapine (Fig. 1) for treatment-resistant
schizophrenia gave rise to a new group of atypical or nonclassical
antipsychotics that have no EPS at the doses frequently used in
therapy and display moderate efficacy towards negative symp-
toms.5 Clozapine exhibits potent affinities for multiple receptors.6
Its action at serotonin (5-HT) receptors is thought to mediate its
beneficial effects on cognition, negative symptoms, and the low
incidence of EPS,7 although it also displays affinity for dopamine
receptors, related to its efficacy on positive symptoms, as well as
The interaction between the 5-HT and dopamine systems has
been proposed to play a critical role in the mechanism of action
of atypical antipsychotic drugs. This is thought to be the case be-
cause the only pharmacological feature which most atypical anti-
psychotic drugs have in common is a relatively potent blockage
of 5-HT2A receptors coupled with a weaker antagonism of the
dopamine D2 receptors.8 This so-called ‘serotonin–dopamine
hypothesis’ has become a useful model for developing new anti-
psychotics to achieve superior efficacy with a lower incidence of
extrapyramidal side effects compared to first-generation (classical)
antipsychotic drugs such as haloperidol and chlorpromazine.9
Although clozapine and other atypical antipsychotic drugs such
as risperidone have brought improvements in treatment of nega-
tive symptoms with lower propensity to elicit EPS, treatment with
these drugs can still lead to substantial weight gain, blood dyscra-
sias, and some movement disorders.10 Additionally, negative
symptoms and cognitive impairments are not fully addressed by
these drugs. Hence, the discovery of a more effective, side-effect-
free therapy for the treatment of schizophrenia remains a challeng-
ing research goal.
As part of our ongoing work on the development of strategies
for the preparation of new D2/5-HT2A receptor antagonists as atyp-
ical antipsychotics,11 we explored the possibility of synthesizing
conformationally constrained analogues of aminobutyrophenones
in which the phenyl ring was replaced by a pyrimidine to form a
tetrahydroquinazolinone system (Fig. 2). The replacement was
made based on the observation that the substitution of –CH@ by
for a-adrenergic, muscarinic, and histaminergic (H1) receptors.
q
This is the 40th paper in the series ‘synthesis, CNS activity of conformationally
restricted butyrophenones’; for preceding paper, see Ref. 11.
* Corresponding author. Tel.: +34 981563100; fax: +34 981594912.
E-mail address: christianf.masaguer@usc.es (C.F. Masaguer).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.041

6060
L. Carro et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6059–6062
Figure 1. Structures of some antipsychotics.
–N@ in aromatic rings has been one of the most-successful appli-
cations of classical isosterism.12 In the present Letter, we report
the synthesis of this new series of tetrahydroquinazolinone deriv-
atives as conformationally constrained aminobutyrophenones and
the evaluation of their affinity towards several dopamine and sero-
tonin receptors.
Figure 2.
We initiated the synthesis of the tetrahydroquinazolinones 18–
21 (Scheme 1) via the condensation of 5-(methoxymethyl)cyclo-
hexane-1,3-dione 113 or 5-(benzyloxymethyl)cyclohexane-1,3-
dione 214 with N,N-dimethylformamide dimethylacetal (DMFDMA)
to obtain aminoketones 3 and 4, respectively, with a yield of 95%.
Compound 3 was transformed into tetrahydroquinazolinones 5–8
at yields between 60% and 70% by employing a tandem Michael
addition–elimination/cyclodehydration process using different
amidine derivatives in AcOH or EtONa/EtOH at reflux. Alterna-
tively, benzylketone 4 was condensed with S-methylthiourea in
AcOH to obtain the methylthiotetrahydroquinazolinone 9 in 50%
yield. The methyl ether group of each tetrahydroquinazolinone
5–8 was cleaved using a 1.0 M solution of BBr3 in CH2Cl2 at
À40 °C to rt, affording the corresponding alcohols 10–13 at accept-
able yields. More forceful conditions (2 mol equiv BBr3, higher
temperatures, or longer reaction times) or the use of other re-
agents, such as iodotrimethylsilane, provided a mixture of decom-
posed products. Alternatively, hydroxymethylquinazolinone 11
could be accessed at 50% yield via the debenzylation of compound
9 using iodotrimethylsilane in CH2Cl2.
Tosylation of alcohols 10–13 under standard conditions fur-
nished the corresponding sulfonates 14–17 in 62–88% yield. Final-
ly, tosylates 14–17 were converted into the required amines 18a–b
to 21a–b by nucleophilic displacement of the tosyl group with the
corresponding substituted piperidines a or b (Scheme 1) at low to
moderate yields.15
The affinities of the compounds 18a,b–21a,b for cloned human
D2 and 5-HT2A receptors (Table 1) were evaluated in in vitro bind-
ing assays using the radioligands [3H]spiperone and [3H]ketan-
serin, respectively, according to our previously described
procedures.16 Ki values (expressed as pKi) were calculated accord-
ing to the Cheng–Prusoff equation.17 In addition, cLog P values and
Scheme 1. Reagents and conditions: (a) DMFDMA, THF, 80 °C, 3 h, 95%; (b) R2C(NH)NH2, AcOH or EtONa/EtOH, reflux, 50–70%; (c) for 5–8: 1 M BBr3, CH2Cl2, À40 °C to rt,
24 h, 45–97%; for 9: TMSI, CH2Cl2, rt, 15 h, 50%; (d) TsCl, Py, rt, 24 h, 62–88%; (e) HNR3R3, dioxane or benzene, reflux, 10–60%.

L. Carro et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6059–6062
6061
Table 1
Results for the calculated properties of compounds 18a,b–21a,b and binding assays (pKi) with D2 and 5-HT2A receptors in CHO cellsa
Compound
Code
R2
cLog Pb
PSAc (Å2)
pKi D2
pKi 5-HT2A
pKi ratio 5-HT2A/D2
18a
18b
19a
19b
20a
20b
21a
21b
QF3504B
QF3508B
QF3514B
QF3518B
QF3524B
QF3528B
QF3564B
QF3568B
H
H
1.1
1.4
2.8
3.1
2.4
2.7
3.2
3.5
3.8
4.1
2.7
63.16
72.12
63.16
72.12
75.19
84.15
63.16
72.12
40.54
35.16
64.17
6.20 0.50
6.80 0.60
NA
7.49 0.09
6.63 0.08
7.31 0.20
NA
7.47 0.18
9.22 0.12
6.65 0.17
8.21d
6.51 0.32
7.63 0.13
6.99 0.44
8.34 0.15
8.19 0.12
8.62 0.10
6.20 0.20
6.90 0.30
6.78 0.25
8.04 0.31
9.30 0.25
1.05
1.12
—
1.11
1.23
1.18
—
0.92
0.73
1.21
1.13
CH3S
CH3S
CH3NH
CH3NH
Ph
Ph
Haloperidol
Clozapine
Risperidone
a
b
c
Values are means of two separate experiments. NA = not active (less than 60% inhibition in radioligand binding at 10
Partition coefficients (cLog P) were calculated using ChemDraw Ultra, version 11.0.1, CambridgeSoft 2007.
Polar surface area (PSA) was calculated using an algorithm developed by Ertl et al.19
Value taken from Ref. 24.
lM).
d
polar surface areas (PSA) were calculated for the novel compounds
described to provide a measure of lipophilicity and predicted brain
penetration, respectively.18,19
properties:21 (a) PSA <90 Å2; (b) HBD <3; (c) cLog P 2–5; (d) molec-
ular weight (MW) <450 Da. For the abovementioned four com-
pounds (18b, 19b, 20a, and 20b), the cLog P values are less than
4 (from 1.4 to 3.1) and the PSA values are in the range of 60–85 (Ta-
ble 1). These values predict drug-like properties22 and the potential
to penetrate the BBB.
With respect to the D2 receptor, compounds bearing a 6-fluor-
obenzisoxazolylpiperidine moiety (amine b) showed higher affini-
ties than those with a 4-fluorobenzoylpiperidine fragment (amine
a), due to the presence of substituents (phenyl, methylthio, or
methylamino) on the tetrahydroquinazolinone core favourable
for affinity. Among 4-fluorobenzoylpiperidine derivatives, com-
pounds 18a and 20a exhibited a modest affinity for the dopamine
D2 receptors as compared to haloperidol or risperidone but were
similar to that of clozapine, while compounds 19a and 21a did
not display affinity towards D2 receptors and therefore should
not be considered as potential antipsychotics.
Regarding the 5-HT2A receptor, the 6-fluorobenzisoxazolylpi-
peridine derivatives (18b, 19b, 20b, and 21b) also showed higher
affinities than compounds with a 4-fluorobenzoylpiperidine frag-
ment (18a, 19a, 20a, and 21a). The compounds with a phenyl sub-
stituent on the tetrahydroquinazolinone moiety (21a and 21b)
displayed lower affinities for the 5-HT2A receptor than the corre-
sponding compounds with methylthio, methylamino, or no sub-
stituents, suggesting a potential steric effect of the phenyl ring in
the binding site. Compounds bearing a methylamino substituent
(20a and 20b) showed the highest affinities for 5-HT2A receptors.
This behaviour could be attributed to the presence of an NH group
in 20 (lacking in compounds 18, 19, and 21), which could establish
an additional interaction with an acceptor group in the 5-HT2A
receptor binding site.
In line with the multiple receptor-targeting approach for the
development of new antipsychotic agents, tetrahydroquinazoli-
nones 18b, 19b, and 20b were selected among the new compounds
because: (a) their Ki values <30 nM (or pKi >7.50) against 5-HT2A
receptors are promising, (b) they exhibit a good 5-HT2A/D2 pKi ratio
(higher than 1.10), (c) they bear different substituents at position 2
of the tetrahydroquinazolinone system, and (d) in general, the
compounds bearing an amine b display higher affinities for the
5-HT2A and D2 receptors than those with an amine a. These chosen
compounds were examined further for binding affinity toward D1,
D3, and 5-HT2C receptors by competition assays using
[3H]SCH23390, [3H]spiperone, and [3H]mesulergine, respectively
(Table 2). D1 receptor hypoactivity in the frontal cortical area has
recently been suggested to contribute to negative symptoms and
impaired cognitive function.23 Thus, D1 receptor-selective agonists
may represent an exciting direction for the treatment of schizo-
phrenia.24 On the other hand, a preferential blockage of D3 versus
D2 receptors has been associated with a relatively benign effect
upon motor function, as compared with drugs possessing D2/D3
or principally D2 antagonist properties.25 Lastly, 5-HT2C receptors
have been suggested to be involved in the weight gain associated
with the treatment of schizophrenia via atypical antipsychotic
drugs.26
In general, the new compounds displayed higher affinity for the
serotonin 5-HT2A receptor [pKi values ranging between 6.20 (21a)
and 8.62 (20b)] than for the dopamine D2 receptors. For example,
20a and 20b were about 35-times and 20-times more potent
against 5-HT2A than D2 receptors, respectively. On the basis of
the 5-HT2A/D2 antagonism hypothesis, it is worth highlighting
compounds 18b, 19b, 20a, and 20b, with Meltzer’s ratios between
1.11 and 1.23, as potential atypical antipsychotics.8
Compound 18b displayed lower affinity than 19b or 20b for
dopamine D1, D2, and D3 receptors, as well as for serotonin 5-
HT2A receptors. Again, the presence of a methylthio or methyl-
amino substituent on the pyrimidine ring favoured an interaction
with the receptor binding sites. Compounds 19b and 20b showed
similar affinities for the new receptors assayed, although the affin-
For antipsychotics, as with the great majority of drugs aimed at
CNS targets, the blood–brain barrier (BBB) must be crossed in order
for a therapeutic effect to be exerted. To predict the BBB penetra-
tion of a compound, the most important molecular descriptors
used are polar surface area (PSA) and lipophilicity [as determined
by the calculated log of the octanol/water partition coefficient
(cLog P)], although the number of hydrogen bond donors (HBDs)
appears also to be a significant feature that distinguishes drugs
marketed for CNS indications from those intended for peripheral
targets.20 Four simple physicochemical rules are accepted to en-
hance the probability of obtaining favourable BBB permeability
Table 2
Human receptor binding affinities (pKi) of compounds 18b, 19b, and 20ba
Compound
pKi D1
pKi D2
pKi D3
pKi 5-HT2A
pKi 5-HT2C
18b
19b
20b
Haloperidol
Clozapine
Risperidone
6.87
7.48
7.37
8.21
7.67
6.83b
6.80
7.49
7.31
9.22
6.65
8.21
6.55
7.35
6.70
7.94
6.04
7.79b
7.50
8.34
8.62
6.78
8.04
9.30
6.30
<5
<5
5.14
7.98
8.13
a
Values are means of two or three separate competition experiments.
Binding data obtained from Ref. 27.
b

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L. Carro et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6059–6062
11. (a) Aranda, R.; Villalba, K.; Raviña, E.; Masaguer, C. F.; Brea, J.; Areias, F.;
Dominguez, E.; Selent, J.; Lopez, L.; Sanz, F.; Pastor, M.; Loza, M. I. J. Med. Chem.
2008, 51, 6085; (b) Dezi, C.; Brea, J.; Alvarado, M.; Raviña, E.; Masaguer, C. F.;
Loza, M. I.; Sanz, F.; Pastor, M. J. Med. Chem. 2007, 50, 3242.
12. (a) Wermuth, C. G. In The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.,
2nd ed.; Academic Press: Amsterdam, 2003; p 193; (b) Patani, G. A.; LaVoie, E. J.
Chem. Rev. 1996, 96, 3147; (c) Kier, L. B.; Hall, L. H. Chem. Biodiv. 2004, 1, 138.
13. Pita, B.; Masaguer, C. F.; Raviña, E. Tetrahedron Lett. 2000, 41, 9835.
14. Masaguer, C. F.; Ravina, E.; Fontenla, J. A.; Brea, J.; Tristan, H.; Loza, M. I. Eur. J.
Med. Chem. 2000, 35, 83.
ity of 19b for the D3 receptor was 4.5-times higher than that of
20b. Taken together, the data point to 19b as a better candidate
for improving negative symptoms in schizophrenia.25 The tetrahy-
droquinazolinone 19b possessed comparable affinity for the three
dopamine receptors tested, high affinity for 5-HT2A receptors, and
did not display affinity towards 5-HT2C receptors, thereby showing
the best overall receptor binding profile. Moreover, the low affinity
of both 19b and 20b for the 5-HT2C receptor (pKi <5) compared to
risperidone (pKi = 8.13) and clozapine (pKi = 7.98) could cause a
possible decrease in the propensity of these compounds to elicit
treatment-caused weight gain.
In summary, new conformationally constrained butyrophenone
analogues with the tetrahydroquinazolinone motif have been syn-
thesized, and their binding affinities determined. Among the com-
pounds surveyed, 19b was identified as the best candidate based
on its good binding affinities for D1, D2, and D3 receptors, high
affinity for 5-HT2A, and low affinity for 5-HT2C receptors, as well
as a Meltzer’s ratio characteristic of an atypical antipsychotic pro-
file. Moreover, cLog P and PSA suggest that this compound has the
potential to penetrate the blood–brain barrier. Further studies on
this series, including in vivo assays to determine antipsychotic
activity, are in progress and will be reported in due course.
15. Data for selected compounds: Compound 18a: Mp 151–153 °C. IR (KBr):
m 1697,
1677, 1596, 1576. 1H NMR (CDCl3, 300 MHz): d 1.80–1.83 (m, 4H); 2.10–2.25
(m, 2H); 2.43–2.50 (m, 4H); 2.80–2.95 (m, 4H); 3.10–3.30 (m, 2H); 7.14 (t,
J = 8.5 Hz, 2H); 7.96 (dd, J = 5.5, 8.6 Hz, 2H); 9.19 (s, 1H); 9.24 (s, 1H). MS (EI):
m/z 367 (M+). Compound 18b: Mp 139–140 °C. IR (KBr):
m 1691, 1611, 1576,
1140. 1H NMR (CDCl3, 300 MHz): d 2.02–2.27 (m, 6H); 2.42–2.68 (m, 4H);
2.86–3.12 (m, 5H); 3.28–3.35 (dd, J = 2.7, 18.0 Hz, 1H); 7.07 (dt, J = 2.0, 8.8 Hz,
1H); 7.25 (dd, J = 2.0, 8.5 Hz, 1H); 7.60–7.70 (dd, J = 5.1, 8.7 Hz, 1H); 9.19 (s,
1H); 9.23 (s, 1H). MS (EI): m/z 381 (MH+). Compound 19a: Mp 155–157 °C. IR
(KBr):
m
1681, 1622, 1564, 1408. 1H NMR (CDCl3, 300 MHz): d 1.81–1.83 (m,
4H); 2.09–2.22 (m, 2H); 2.32–2.50 (m, 4H); 2.62 (s, 3H); 2.75 (dd, J = 9.4,
17.8 Hz, 1H); 2.79–2.91 (m, 3H); 3.14–3.24 (m, 2H); 7.13 (t, J = 8.6 Hz, 2H);
7.96 (dd, J = 5.4, 8.9 Hz, 2H); 8.95 (s, 1H). MS (CI): m/z 414 (MH+). Compound
19b: Mp 224–225 °C (hydrochloride salt). IR (KBr):
m 1687, 1614, 1564, 1410,
1274, 1176. 1H NMR (CDCl3, 300 MHz): d = 2.02–2.04 (m, 4H); 2.22–2.27 (m,
2H); 2.35–2.49 (m, 4H); 2.61 (s, 3H); 2.77 (dd, J = 9.5, 18.0, 1H); 2.83–2.88 (m,
1H); 2.95–3.06 (m, 3H); 3.17–3.23 (m, 1H); 7.07 (dt, J = 2.2, 8.8 Hz, 1H); 7.23
(dd, J = 2.0, 8.5 Hz, 1H); 7.68 (dd, J = 5.1, 8.7 Hz, 1H); 8.95 (s, 1H). MS (EI): m/z
426 (M+). Compound 20a: Mp >230 °C (hydrochloride salt). IR (KBr):
m 3290,
1674, 1621, 1590, 1287. 1H NMR (CDCl3, 300 MHz): d 1.82 (br s, 4H); 2.06–2.20
(m, 2H); 2.28 (dd, J = 10.5, 16.4 Hz, 1H); 2.37 (br s, 3H); 2.61–2.74 (m, 2H);
2.88–3.03 (m, 3H); 3.08 (d, J = 5.1 Hz, 3H); 3.16 (dd, J = 7.8, 15.0 Hz, 1H); 5.85
(br s, 1H); 7.13 (t, J = 8.6 Hz, 2H); 7.96 (dd, J = 5.4, 8.8 Hz, 2H); 8.78, 8.88 (2 Â s,
Acknowledgements
1H). MS (CI): m/z 397 (MH+). Compound 20b: Mp 190–191 °C. IR (KBr):
m 3261,
This work was supported by the Spanish Ministerio de Educa-
ción y Ciencia (Grants SAF2005-08025-C01 and SAF2005-08025-
C03) and Xunta de Galicia (Grants PGIDIT06PXIC203104PN and
1678, 1599, 1411. 1H NMR (CDCl3, 300 MHz): d 2.04–2.22 (m, 6H); 2.32 (dd,
J = 10.6, 16.3 Hz, 1H); 2.43 (br s, 3H); 2.64–2.80 (m, 2H); 2.99–3.07 (m, 4H);
3.09 (d, J = 5.1 Hz, 3H); 5.77 (br s, 1H); 7.07 (dt, J = 2.2, 8.8 Hz, 1H); 7.25 (dd,
J = 2.1, 8.4 Hz, 1H); 7.70 (dd, J = 5.2, 8.4 Hz, 1H); 8.80, 8.92 (2 Â s, 1H). MS (EI):
PGIDIT06PXIC203051PN).
A Ph.D. fellowship (FPU) has been
m/z 409 (M+). Compound 21a: Mp 170–172 °C. IR (KBr):
m 1690, 1675, 1601,
granted to L. Carro by the Ministerio de Educación y Ciencia.
1567. 1H NMR (CDCl3, 300 MHz): d 1.81–1.86 (m, 4H); 2.15–2.28 (m, 2H);
2.40–2.57 (m, 4H); 2.85–2.98 (m, 4H); 3.19–3.26 (m, 1H); 3.31–3.38 (m, 1H);
7.13 (t, J = 8.6 Hz, 2H); 7.47–7.54 (m, 3H); 7.96 (dd, J = 5.4, 8.9 Hz, 2H); 8.51–
8.54 (m, 2H); 9.24 (s, 1H). MS (EI): m/z 443 (M+). Compound 21b: Mp 179–
References and notes
181 °C. IR (KBr):
m
1690, 1615, 1580, 1143. 1H NMR (CDCl3, 300 MHz): d 2.04–
2.11 (m, 4H); 2.17–2.29 (m, 2H); 2.43-2.61 (m, 4H); 2.88–3.11 (m, 5H); 3.34–
3.42 (m, 1H); 7.08 (dt, J = 2.1, 8.8 Hz, 1H); 7.24 (dd, J = 2.1, 8.9 Hz, 1H); 7.50–
7.55 (m, 3H); 7.71 (dd, J = 5.2, 8.7 Hz, 1H); 8.52–8.55 (m, 2H); 9.26 (s, 1H). EM
(IE): m/z = 456 (M+).
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