Aromatic ring functionalization of benzolactam derivatives: New potent dopamine D3 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2010.12.083

Since the discovery of the dopamine D₃ receptor, an intensive effort has been directed toward the development of potent and selective ligands in order to elucidate the function and potential therapeutic advantages of targeting D₃ rec

Full text of DOI:10.1016/j.bmcl.2010.12.083

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2670–2674
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Aromatic ring functionalization of benzolactam derivatives: New potent
dopamine D3 receptor ligands
Raquel Ortega a,*, Harald Hübner b, Peter Gmeiner b, Christian F. Masaguer a
a Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain
b Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, D-91052 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Since the discovery of the dopamine D3 receptor, an intensive effort has been directed toward the devel-
opment of potent and selective ligands in order to elucidate the function and potential therapeutic
advantages of targeting D3 receptors. As a part of our efforts, a novel series of substituted benzolactams
derivatives was synthesized mostly through palladium-catalyzed reactions. Their affinities on D1–D4
receptors were evaluated and the data led us to highly potent D3 ligands, some of them highly selective
for D3 receptor, compared to the related dopamine receptor subtypes. Functional D3 activity assays of the
most relevant compounds have been carried out revealing antagonist as well as partial agonist activity.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 October 2010
Revised 14 December 2010
Accepted 16 December 2010
Available online 22 December 2010
Keywords:
Dopamine receptors
Antipsychotics
Structure–activity relationship
Benzolactams
Arylpiperazines
The D3 dopamine receptor was first identified and cloned by
Sokoloff et al.1 in 1990 and has been shown to be an interesting
target for different CNS diseases. Although its structure and phar-
macology are very similar to dopamine D2, the D3 receptor is gen-
erally less abundant than the D2 receptor, and the difference is
particularly striking in the caudate putamen, where D2 receptors
are displayed at high density, whereas D3 receptors are poorly rep-
resented.2 Moreover, D3-binding sites and mRNA encoding D3
receptors are concentrated in the limbic brain areas known to be
associated with cognitive and emotional functions.3 Due to this
observation, the D3 receptor has been suggested to be a potential
target in the treatment of neurological disorders such as schizo-
phrenia,4,5 Parkinson’s disease,6 drug-induced dyskinesia,7 and
drug abuse.8 Moreover, recent studies have shown that proerectile
effects of dopamine D2-like agonists are mediated by the D3 recep-
tor in rats and mice.9
In an attempt to prove these hypotheses, an intensive effort has
been directed toward the development of selective ligands for
dopamine D3 receptors.8,10 A large number of compounds with var-
ious selectivities for the D3 receptor have been developed. Some of
the well known D3 agonists include pramipexole and ropinirole
(Fig. 1), and these agonists were shown to exhibit a 4–10-fold high-
er affinity for the D3 than D2 receptor.11
selectivity for the D3 receptor (Fig. 2). Most of these compounds
contain a piperazine ring connected to a suitable benzamide-type
moiety via variable linker size.10,12
Today there is an urgent need for more selective molecular tools
to facilitate a relevant differentiation between D3 actions and those
mediated by the D2 receptors, in order to elucidate the function
and potential therapeutic advantages of targeting D3 receptors.
We have previously reported the synthesis and binding affinity
of a new series of DA D2/D3 receptor ligands (Fig. 3) based on the
benzolactam scaffold.13
These compounds maintain three characteristic elements of
many dopamine D3 receptor antagonists: (1) an amine moiety,
(2) a spacer, usually a linear alkyl chain, and (3) a hydrophobic res-
idue, often connected through an amide bond. The size of the lac-
tam cycle varied from a six to eight-membered ring, the length of
the alkyl spacer, from propyl to pentyl, and the aryl substituent of
the piperazine ring was varied to achieve a set of compounds that
allows us to evaluate some of the structural requirements for high
binding affinity and selectivity on the D3 receptor. One of our
long-term objectives in this project is to develop a reliable
N
On the other hand, numerous ligands as antagonists have been
developed so far with a number of lead compounds showing high
N
HN
O
NH2
S
N
H
Pramipexole
Ropinirole
⇑
Corresponding author.
E-mail address: raquel.ortega@usc.es (R. Ortega).
Figure 1. Structures of the D3 dopamine agonists pramipexole and ropinirole.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.083

R. Ortega et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2670–2674
2671
NHCOCH3
O
N
N
NC
N
O
N
N
S33138
i D3 2 nM
D2/D3 37
H
K
O
GR 103691
i D3 0.32 nM
D2/D3 130
O
K
O
H
N
N
O
N
Cl
N
Cl
N
N
O
H
S
SB 414796
i D3 4 nM
D2/D3 100
FAUC365
i D3 0.5 nM
D2/D3 7200
K
MeO2S
K
N
N
N
N
N
F3C
S
S
N
F
F
N
N
H
I
O
N
S
N
F
(GSK)
N
K
i D3 0.25 nM
ABT 925
D2/D3 1000
K
i D3 2.9 nM
D2/D3 200
O
N
OH
N
N
N
N
CF3
N
H
NH
N
Cl
Cl
H
R
-PG648
i D3 2.9 nM
D2/D3 200
II
K
K
i D3 0.76 nM
D2/D3 256
Figure 2. Structures of selective D3 receptor ligands.
widely described. Nevertheless, the particular reaction conditions
had to be optimized depending on the starting compounds. In
our case, the best results were obtained when 3, or 4 were coupled
with phenyl-, 2-thienyl-, or 2-furylboronic acid in deionized water
using Pd(AcO)2 as catalyst in the presence of K2CO3 and Bu4NBr.14
Under these conditions, the 6-arylbenzolactams (5–8) were ob-
tained in 75–96% yield. Coupling the more deactivated 4-pyr-
idylboronic acid required Pd(Ph3P)4 as catalyst15 yielding 9 in
79% yield (Table 2, entry 5).
Figure 3. General structure of benzolactam derivatives.
pharmacophore model for these compounds with which we would
be able to rationalize the observed DA D2/D3 binding affinities and
selectivities of our compounds.
In our further quest to understand the role of the benzolactam
ring and the effect of different substitutions in the fused-benzene
ring, we have designed a new series of compounds where the ben-
zene ring of the benzolactam motif has been functionalized by the
introduction of different substituents, mostly through a palladium-
catalyzed reaction.
The expansion of the substituted benzocycloalkanones 1, 2,
10–13, and 16 (Scheme 1) for obtaining the corresponding 1-
oxo-2H-benzolactams 3, 4, and 17–21 was carried out by means
of Schmidt reaction. The success of this reaction is dependent of
several variables such as the solvent, the acid, or the starting mate-
rial. In our case, the best results were achieved when a 1:1 mixture
of CH2Cl2 and methanesulfonic acid as solvent, and 2 equiv of NaN3
were used. In the case of 6-methoxytetralone (13) the expansion
was carried out more productively in concentrated HCl (Table 1).
In all cases, the corresponding isomeric 2-oxo-1H-benzolactams
were also isolated in lower quantity.
Cyanation reaction of bromide 3 was also performed with
Zn(CN)2 and Pd(PPh3)4 in DMF to obtain the corresponding aromatic
nitrile (Table 2, entry 6). However, repeated assays where cyanide
sources, catalysts, or solvents were varied afforded poor yields
(<10%) of the 6-cyanobenzolactam 19. Alternatively, for obtaining
this compound, we decided to reverse the order of the steps: cyana-
tion of 5-bromoindanone (1) with CuCN in DMF yielded 5-cyano-
indanone (10, 52%), which was transformed in the corresponding
lactam 19 by Schmidt rearrangement in 55% yield, providing better
overall yield and a more efficient purification.
The same problems were found for palladium-catalyzed ethyny-
lation of bromolactame 3 (Table 2, entry 7), where ethynylbenzolac-
tam 20 was isolated in a poor 5% yield. Therefore, Sonogashira
coupling between bromoindanone 1 and TMS–acetylene was
attempted using Pd(PPh3)2Cl2 as the catalyst and CuI in 3:1 triethyl-
amine/DMF. 5-(Trimethylsilylethynyl)-2,3-dihydroinden-1-one
was obtained in 46% yield, which upon alkaline hydrolysis with
K2CO3 in MeOH gave 5-ethynyl-2,3-dihydroinden-1-one (11) in
56% yield.
Due to the better pharmacological outcomes demonstrated in
previous studies13 by compounds bearing a 7-membered lactam,
the 2,3,4,5-tetrahydro-7-(2-thienyl)benzo[c]azepin-1-one (21)
The substitution of the bromine atom in arylbromides for differ-
ent boronic acids using Pd(0) as catalyst (Suzuki reaction) has been

2672
R. Ortega et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2670–2674
O
O
O
(ii)
(vii)
TfO
HO
S
16
(i)
15
14
(vi)
O
O
O
O
(iii)
(i)
(i)
NH
m
R1
R1
m
R1
R1
R2
17: R1 = CH3O, m = 2
12: R1 = F, m = 1
10: R1 = N≡ C
1: R1 = Br, R2 = H
18: R1 = F, m = 1
13: R1 = CH3O, m = 2
11: R1 = HC≡ C
2: R1 = H, R2 = Br
19: R1 = N≡ C, m = 1
20: R1 = HC≡ C, m = 1
21: R1 = 2-Thienyl, m = 2
(i)
(iv)
O
O
O
O
N
N
Cl
N
O
(ii)
(iv)
(v)
NH
NH
N
R1
R1
R1
R1
m
m
R2
R2
R2
R2
32: R1 = CH3O, R2 = H, m = 2
33: R1 = F, R2 = H, m = 1
22: R1 = CH3O, R2 = H, m = 2
23: R1 = F, R2 = H, m = 1
5: R1 = Ph, R2 = H
3: R1 = Br, R2 = H
4: R1 = H, R2 = Br
6: R1 = H, R2 = Ph
34: R1 = Ph, R2 = H, m = 1
35: R1 = H, R2 = Ph, m = 1
36: R1 = 2-Furyl, R2 = H, m = 1
24: R1 = Ph, R2 = H, m = 1
7: R1 = 2-Furyl, R2 = H
8: R1 = 2-Thienyl, R2 = H
9: R1 = 4-Pyridyl, R2 = H
25: R1 = H, R2 = Ph, m = 1
26: R1 = 2-Furyl, R2 = H, m = 1
27: R1 = 2-Thienyl, R2 = H, m = 1
28: R1 = 4-Pyridyl, R2 = H, m = 1
29: R1 = NC, R2 = H, m = 1
30: R1 = HC C, R2 = H, m = 1
31: R1 = 2-Thienyl, R2 = H, m = 2
37: R1 = 2-Thienyl, R2 = H, m = 1
38: R1 = 4-Pyridyl, R2 = H, m = 1
39: R1 = NC, R2 = H, m = 1
40: R1 = HC C, R2 = H, m = 1
41: R1 = 2-Thienyl, R2 = H, m = 2
Scheme 1. Reagents and conditions: (i) NaN3 (2 equiv), 1:1 CH3SO3H/CH2Cl2 (or HCl for 17), 0 °C 1 h, rt, 12 h; (ii) for 5–8, and 16: boronic acid, Bu4NBr, K2CO3, Pd(AcO)2, H2O,
70 °C, 2–4 h; for 9: 4-pyridylboronic acid, 2 M K2CO3 (aq), Pd(Ph3P)4, 1:1 EtOH/toluene, 90 °C, 5 h; (iii) for 10: CuCN, DMF, reflux, 24 h; for 11: (a) TMS-C„CH, Pd(PPh3)2Cl2,
CuI, 3:1 Et3N/DMF; (b) K2CO3, MeOH; (iv) 1-bromo-4-chlorobutane, NaH, benzene, reflux, 24–48 h; (v) 1-(2-methoxyphenyl)piperazine, K2CO3, KI, methylisobutylketone,
reflux, 48 h; (vi) 13, AlCl3, CH2Cl2, reflux, 24 h; (vii) 14, trifluoromethane sulfonic anhydride, anhydrous pyridine, 0 °C 10 min, rt 40 h.
Table 1
Reaction conditions of Schmidt reaction for the preparation of substituted benzolactams
Ketone
Reagent (equiv)
Solvent
Temp (°C)
Time (h)
Product (yield)
R1
R2
N
1
2
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
Methanesulfonic acid:CH2Cl2
Methanesulfonic acid:CH2Cl2
Methanesulfonic acid:CH2Cl2
Methanesulfonic acid:CH2Cl2
Methanesulfonic acid:CH2Cl2
HCl (c)
rt
rt
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
3 (47%)
4 (46%)
Br
H
NC
HC„C
F
H
Br
H
H
H
H
H
1
1
1
1
1
2
2
10
11
12
13
16
19 (55%)
20 (37%)
18 (48%)
17 (60%)
21 (35%)
CH3O
2-Furyl
Methanesulfonic acid:CH2Cl2
Table 2
Reaction conditions of palladium-catalyzed cross-coupling reaction for the synthesis of new substituted benzolactams
Entry Reactant Reagent
Catalyst system (equiv) Base
Additives Solvent
H2O
Temp (°C) Time (h) Product (yield) R1
R2
1
2
3
4
5
6
7
8
9
3
4
3
3
3
3
3
1
15
PhB(OH)2
PhB(OH)2
(2-Furyl)B(OH)2
(2-Thienyl)B(OH)2 Pd(AcO)2 (1%)
(4-Pyridyl)B(OH)2
Zn(CN)2
(HC„C)SiMe3
(HC„C)SiMe3
Pd(AcO)2 (1%)
Pd(AcO)2 (1%)
Pd(AcO)2 (1%)
K2CO3 Bu4NBr
K2CO3 Bu4NBr
K2CO3 Bu4NBr
K2CO3 Bu4NBr
70
70
70
70
2.5
2.5
2.5
2.5
5
5 (75%)
6 (96%)
7 (81%)
8 (83%)
9 (79%)
19 (7%)
20 (5%)
11 (44%)
16 (65%)
Ph
H
2-Furyl
2-Thienyl
4-Pyridyl
N„C
H
Ph
H
H
H
H
H
H
H
H2O
H2O
H2O
Pd(PPh3)4 (6%)
K2CO3
—
Et3N
Et3N
—
EtOH/toluene 90
Pd(PPh3)4 (10%)
(PPh3)2PdCl2 (4%)
(PPh3)2PdCl2 (4%)
—
DMF
100
6
CuI
CuI
Et3N/THF
Et3N/DMF
H2O
rt
80
70
15
16
2.5
HC„C
HC„C
2-Furyl
(2-Thienyl)B(OH)2 Pd(AcO)2 (1%)
K2CO3 Bu4NBr
was synthesized in four steps from 13. Starting with the cleavage
of the methoxy group with AlCl3 (5 equiv) in CH2Cl2, the alcohol
14 was obtained in 83% yield. Then, triflate 15 was generated in
74% yield by treating 14 with trifluoromethanesulfonic anhydride
in pyridine. Substitution of the triflate group in 15 for 2-thienyl
was carried out by Suzuki reaction using the same conditions as
for compound 8 (Table 2, entry 4): 2-thienylboronic acid, Pd(AcO)2,
K2CO3 and Bu4NBr, affording the desired ketone 16 in 65% yield

R. Ortega et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2670–2674
2673
(Table 2, entry 9). Subsequently, lactam 21 was synthesized from
ketone 16 by Schmidt rearrangement in 35% yield (Table 1).
The differently substituted benzolactams 5–9, and 17–21 were
alkylated with 1-bromo-4-chlorobutane in anhydrous benzene
using NaH as a base to give the corresponding 4-chlorobutylamides
22–31 in good yields (62–90%). Finally, subsequent displacement
of the chlorine atom by o-methoxyphenylpiperazine in methyli-
sobutylketone with K2CO3 as a base and KI in catalytic amount fur-
nished the final products (32–41) in 35–80% yield.
14-fold increase of D3 affinity and at the same time a clear
enhancement of D3 selectivity over D2 (5- to 27-fold) and D4
(13- to 25-fold). Best D3 affinity could be determined for the 2-thi-
enyl derivative 37 and the 4-pyridyl analogue 38 both showing a Ki
value of 0.12 nM with compound 38 displaying the best selectivity
pattern of D3 over D2long, D2short and D4 with ratios of 59, 110 and
28, respectively. While for the unsubstituted compounds 42 and
43 a better D3 affinity could be shown for the seven-membered
benzolactam 43 with a Ki value of 0.27 nM, this effect could not
be observed for the 2-thienyl substituted analogues 37 and 41,
when the seven-membered derivative 41 displayed a slightly re-
duced Ki value of 0.29 nM compared to the Ki of 0.12 nM measured
for the six-membered congener 37 and an attenuation of D3 selec-
tivity over D2 (18- and 7-fold for 41 vs 92- and 58-fold for 37).
Interestingly, when shifting the aromatic appendage of the benzo-
lactam from position 6 to position 5 creating a more bended unsat-
urated carboxamide system the binding profile clearly changes.
For the more linearly oriented 6-phenyl benzolactam 34 a subn-
anomolar Ki value of 0.25 nM was measured for D3, whereas the
5-phenyl analogue 35 showed an 48-fold decrease of D3 binding
(Ki = 12 nM) and a change of the selectivity pattern towards a
slightly D4 preference.
As a measure of functional D3 activity, ligand efficacy of repre-
sentative benzolactams 34, 36–38, 42 and 43 was determined by a
mitogenesis assay measuring the rate of [3H]thymidine incorpora-
tion into a CHO dhfrÀ cell line stably expressing the human D3
receptor when the full agonist quinpirole was used as a reference
agent17,21,22 (Table 4). While all tested compounds showed partial
agonist activity with 27–40% of the full agonist effect of the refer-
ence only the 4-pyridyl substituted derivative 38 displayed a neu-
tral antagonist activity. This observation might be explained by the
fact that the introduction of a basic nitrogen in the heteroaromatic
appendage of the benzolactam substructure might let to a distinct
interaction of the ligand with the receptor protein inferring the
conformational change, which is considered to be necessary during
receptor activation.23 Future SAR investigations with compounds
bearing different basic substructures are necessary to confirm this
observation.
Receptor binding experiments were established to evaluate the
binding properties of the newly synthesized lactams 32–41 in
comparison to the recently described compounds 42 and 43
(Table 3). The binding data was generated by measuring their abil-
ity to compete with [3H]spiperone for the cloned human dopamine
receptor subtypes D2long, D2short,
16 D317 and D4.418 stably expressed
in Chinese hamster ovary cells (CHO).19 D1 receptor affinities were
determined utilizing porcine striatal membranes and the D1 selec-
tive radioligand [3H]SCH23390. The ligands were also investigated
for their potency to displace [3H]WAY100635, [3H]ketanserin and
[3H]prazosin when employing porcine 5-HT1A, 5-HT2 and
a1 recep-
tors, respectively.20 While all test compounds show only moderate
affinities to the D1 and 5-HT2 receptor, binding in the two digit and
one digit nanomolar range was determined for the subtypes of D2
and D4, the serotonergic 5-HT1A and the adrenergic a1 receptor.
For all compounds best receptor recognition could be observed
for the D3 receptor, when Ki values in the range form 0.12 to
1.7 nM could be measured. Analyzing the impact of the ring size
of the benzolactams on the binding properties the seven-mem-
bered ligand 43 showed a Ki of 0.27 nM and a more than sixfold
increase of D3 affinity compared to the tetrahydroisoquinolinone
42, but a similar selectivity pattern. Introduction of small residues
like methoxy (in 32) or fluoro (in 33) as well as the unsaturated
moieties like cyano (in 39) or ethynyl (in 40) at position 6 of the
six-membered benzolactam revealed no or only a less distinct
improvement of D3 binding and selectivity in relation to the
unsubstituted analogue 42. In contrast, the extension of the aro-
matic system of the benzolactam with aromatic or heteroaromatic
appendages like phenyl, furyl, thienyl or pyridyl yielded in a 7- to
Table 3
Receptor binding data and selectivity pattern for the test compounds 31–43 at the human dopamine D2, D3 and D4 subtypes as well as the porcine D1, the serotonergic 5-HT1A
,
5-HT2 and adrenergic a1 receptor (Ki values in nM)a
O
N
O
N
N
N
N
O
O
N
( )m
R
32-34, 36-43
35
R
Compound (code)
Binding affinity (Ki values in [nM])
[3H]spiperone [3H]WAY 600135 [3H]ketan-serin [3H]prazo-sin
hD2long hD2short
Structure
R
[3H]SCH 23390
Selectivity
D1/D3 D2long/D3 D2short/D3 D4/D3
m pD1
hD3 hD4 p5-HT1A
p5-HT2
pa1
42 (USC-A401)b
43 (USC-B401)b
32 (USC-J401)
33 (USC-G401)
34 (USC-H401)
35 (USC-N401)
36 (USC-I401)
37 (USC-K401)
41 (USC-P401)
38 (USC-M401)
39 (USC-L401)
40 (USC-O401)
H
H
CH3O
F
Ph
Ph
2-Furyl
2-Thienyl 1 480
2-Thienyl 2 920
4-Pyridyl
N„C
1
2500
2900
2100
2300
640
21
3.9
3.2
26
38
52
16
11
5.1
7.1
38
24
7.0
1.5
0.93
9.2
15
1.7 1.9 2.4
0.27 1.3 1.7
0.27 3.0 2.5
1.6 2.8 1.7
0.25 3.4 38
12 9.8 47
0.21 3.3 19
0.12 2.3 6.2
0.29 2.9 68
0.12 3.4 13
1.3 6.1 3.8
0.50 4.1 14
990
1100
810
840
330
230
330
190
530
160
430
920
2.3
5.7
3.7
3.1
5.4
1.3
1.6
3.7
9.7
2.2
3.8
2.4
1500 12
11,000 14
7800 12
1400 16
2600 150
4.1
5.6
3.4
5.8
60
5.3
23
58
1.1
4.8
11
1.8
14
0.82
16
19
10
28
4.7
8.2
2
2
1
1
—
1
220
580
63
18
4.3
4.8
6.9
2.1
13
22
8.8
2800 77
4000 92
3200 18
3200 59
2500 29
3800 48
7.2
110
17
1
1
1
380
3200
1900
HC„C
17
a
All values are means of two to four individual competition experiments each done in triplicate.
See Ref. 13.
b

2674
R. Ortega et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2670–2674
Table 4
(INSERM, Paris), the late Dr. H. H. M. Van Tol (Clarke Institute of
Psychiatry, Toronto) and Dr. J. Shine (The Garvan Institute of
Medical Research, Sydney) for providing D3, D4.4 and D2 receptor
expressing cell lines.
Intrinsic activities of the representative test compounds 34, 36–38, 42 and 43 and the
reference compound quinpirole derived from the stimulating effect on mitogenesis of
D3 receptor expressing cellsa
[3H]Thymidine uptake (mitogenesis)
Agonist effectb (%)
EC50 (nM)
c
Compound
Supplementary data
42 (USC-A401)
43 (USC-B401)
34 (USC-H401)
36 (USC-I401)
37 (USC-K401)
38 (USC-M401)
Quinpirole
36
34
41
27
40
0
3.3
0.33
3.3
2.3
2.8
—
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.12.083.
References and notes
100
1.4
a
Determined with CHO dhfrÀ mutant cells stably expressing the human D3
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1990, 347, 146.
2. Levant, B. Pharmacol. Rev. 1997, 49, 231.
3. (a) Joyce, J. N.; Miador-Woodruff, J. H. Neuropsychopharmacology 1997, 16, 375;
(b) Shafer, R. A.; Levant, B. Psychopharmacology 1998, 135, 1; (c) Joyce, J. N.
Pharmacol. Ther. 2001, 90, 231.
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receptor.
b
Rate of incorporation of [3H]thymidine as evidence for mitogenesis activity
relative to the maximal effect of the full agonist quinpirole (=100%) used as a
reference.
c
EC50 values derived from a mean curve of four or six independent experiments.
In summary, based on the chemical structure of the benzolac-
tam derivative 43, a compound with high affinity for D3 receptor,
and maintaining the N-(o-methoxyphenyl)piperazine residue,
new benzolactam-containing derivatives have been synthesized
with good overall yields (40–60%). Their affinities on D1–D4 recep-
tors were evaluated to elucidate how substitutions in the benzolac-
tam part of the pharmacophore affect to the affinity or selectivity
for these receptors. The best results were found when H-6 was
substituted by bulky groups, especially aromatic heterocycles. In
this regard, higher D3 affinity could be determined for the 2-thienyl
derivative 37 and the 4-pyridyl analogue 38 both showing a Ki va-
lue of 0.12 nM, with compound 38 displaying the best selectivity
pattern of D3 over D2long, D2short and D4 receptors, with ratios of
59, 110 and 28, respectively. Functional D3 activity assays showed
that while all tested compounds exhibited partial agonist activity
with 27–40% of the full agonist effect of the reference, the 4-pyri-
dyl substituted derivative 38 was displayed as a neutral antagonist,
which might be explained by the fact that the introduction of a
basic nitrogen in the heteroaromatic appendage might infer the
conformational change within the receptor protein, which is neces-
sary for receptor activation.
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Acknowledgements
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We thank the Xunta de Galicia (Ref. PGIDIT06 PXIB203173PR)
for the financial support, and Dr. J.-C. Schwartz and Dr. P. Sokoloff