1,8-Naphthyridin-4-one derivatives as new ligands of A2A adenosine receptors

Article abstract of DOI:10.1016/j.bmcl.2005.06.064

A series of 1,8-naphthyridine derivatives bearing various substituents in position 3, 4, and 7 of the heterocyclic nucleus have been synthesized and evaluated for their affinity at the bovine and human adenosine receptors. The new compounds were found to

Full text of DOI:10.1016/j.bmcl.2005.06.064

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4604–4610
1,8-Naphthyridin-4-one derivatives as new ligands of A2A
adenosine receptors
Clementina Manera,a,* Laura Betti,b Tiziana Cavallini,a Gino Giannaccini,b
Adriano Martinelli,a Gabriella Ortore,a Giuseppe Saccomanni,a Letizia Trincavelli,b
Tiziano Tuccinardia and Pier Luigi Ferrarinia
aDipartimento di Scienze Farmaceutiche, via Bonanno 6, 56126 Pisa, Italy
bDipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, via Bonanno 6, 56126 Pisa, Italy
Received 30 March 2005; revised 23 June 2005; accepted 23 June 2005
Available online 15 August 2005
Abstract—A series of 1,8-naphthyridine derivatives bearing various substituents in position 3, 4, and 7 of the heterocyclic nucleus
have been synthesized and evaluated for their affinity at the bovine and human adenosine receptors. The new compounds were
found to lack the affinity toward A1AR, whereas many of them are able to acquire an interesting affinity and selectivity for the
A
2AAR.
Ó 2005 Elsevier Ltd. All rights reserved.
Adenosine is probably the most important neuromodu-
lator in the central and peripheral nervous systems;1 its
formation usually increases under metabolically favor-
able conditions.2 This nucleoside modulates its effects
through the activation of four subtype receptors located
on cell membranes, known as A1, A2A, A2B, and A3.3
These are members of the seven-strong transmembrane
spanning G-protein-coupled receptors family. Adeno-
sine receptors are associated with different second
messenger systems: in particular, the A2A adenosine
receptor (A2AAR) appears to be almost exclusively
linked with the stimulation of adenylyl cyclase activity.
Its presence in the CNS is abundant in discrete brain re-
gions such as the striatum,4 where an intricate functional
interaction with dopamine receptor signalling occurs.
The blockade of the A2AAR is reported to produce di-
rect effects on D2 receptors;5 consequently, there is the
possibility of using A2AAR antagonists as novel phar-
macological tools in the treatment of acute or chronic
neurological disorders, such as stroke or ParkinsonÕs
disease.6 In the peripheral system, the A2AAR is present
on various tissues7–9 and then A2AAR agonists can be
used to inhibit platelet aggregation in thrombosis, in
ischemia,10,11 and to determine strong anti-inflammato-
ry and immunosuppressive effects.12
In view of all these pharmacological profiles of the
A2AAR, much effort has been directed in the last few
years toward the synthesis of selective A2AAR ligands.
As part of our research aimed at finding new AR selec-
tive antagonists, we recently reported the synthesis and
the binding activity at bovine and native human aden-
osine receptors (A1, A2A, and A3) of 1,8-naphthyridine
derivatives bearing various substituents at the positions
2, 4, and 7 of the heterocyclic nucleus.13,14 The binding
results showed that a large part of the new 1,8-naph-
thyridine derivatives proved to be A1 bovine adenosine
receptor selective, with a high affinity in the low nano-
molar range; on the contrary, all the 1,8-naphthyridine
derivatives generally lost their affinity for the hA1AR,
in some cases to a considerable extent (more than
1000 times).14 As regards the affinity for the bA2AAR,
1,8-naphthyridine derivatives generally possess a mod-
erate affinity, and this remained approximately the
same as for the native hA2AAR.14 In the light of these
results, it appeared to be of interest to introduce struc-
tural modifications into the 1,8-naphthyridine deriva-
tives studied so far, in order to further investigate the
SAR in this class of compounds. For these reasons,
we synthesized 1,8-naphthyridine derivatives and 1,8-
naphthyridin-4-one derivatives of general structures
1–3 bearing various substituents at the positions 3, 4,
Keywords: 1,8-Naphthyridine; Adenosine; Adenosine receptors.
*
Corresponding author. Tel.: +39 050 2219554; fax: +39 050
2219605; e-mail: manera@farm.unipi.it
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.064

C. Manera et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4604–4610
4605
and 7 of the heterocyclic nucleus. It needs to be point-
ed out that the numbering of the 1,8-naphthyridine
nucleus used is the same as that reported for the previ-
ous series.13,14 At the position 3 of the naphthyridine
nucleus, compounds of type 1 are characterized by
the presence of a lipophilic substituent, such as a ben-
zylic or p-chlorobenzylic group, while compounds of
types 2 and 3 are characterized by the presence of an
ester group or an aliphatic or aromatic carboxamide
group; this last group is considered to be an important
structural requirement shown by other classes of
adenosine receptor ligands, such as pyrazolotriazolo-
pyrimidine derivatives15,16 and triazoloquinazoline
derivatives.17 The new compounds (1–3) were found
to lack the affinity towards A1AR, whereas they are
able to acquire an interesting affinity and selectivity
for the A2AAR, therefore, in order to better rationalize
the experimental observations about the quite different
affinity of compounds of types 1–3 for A1AR and
A2AAR, a molecular modeling study was carried out.
Scheme 2. Reagents: (i) anhydrous HCl, ethanol.
The synthesis of compounds of types 1–3 is outlined in
Schemes 1–6.
The treatment of 3-benzyl-4-hydroxy-7-methyl-1,8-
naphthyridine 1a18 with phosphoryl chloride gave the
4-chloro derivative 1b, which by reaction with NaN3
led to the azido derivative 1c. When 1a was refluxed
in toluene with LawessonÕs reagent, the corresponding
mercapto derivative 1d was obtained. Finally, the treat-
ment of 1b with an excess of cyclohexylamine in a
sealed tube at 120 °C gave the 1,8-naphthyridine 1e
(Scheme 1).
Scheme 3. Reagents: (i) 10% NaOH; (ii) C6H5CH2OH, NaHCO3,
anhydrous DMF; (iii) RNH2.
As reported in Scheme 2, the 7-methyl-2,3-dihydro-1,8-
naphthyridin-4(1H)-one (1g),19 by reaction with o-chlo-
robenzaldehyde and anhydrous hydrogen chloride,
provided the 3-benzyl and 3-benzylidene derivatives
1h and 1i, respectively, which were separated by flash
chromatography.
Scheme 4. Reagents: (i) H2, Pd/C, glacial AcOH; (ii) Ac2O; (iii)
C6H5COCl.
Scheme 1. Reagents and conditions: (i) POCl3, 80 °C, 4 h; (ii) NaN3,
DMF, 130 °C, 5 min; (iii) LawessonÕs reagent, toluene, reflux, 4 h; (iv)
cyclohexylamine, 120 °C, 24 h.
Scheme 5. Reagents: (i) p-ClC6H4CH2NH2.

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C. Manera et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4604–4610
Scheme 6. Reagents: (i) Ac2O; (ii) NaNO2, H2SO4; (iii) NaNO2, HCl; (iv) NaNO2, HBr; (v) H2, Pd/C; (vi) alkyl or cycloalkyl amines.
The reaction of the 7-methyl-1,8-naphthyridin-4(1H)-
on-3-carboxylic acid ethyl ester (2a)20 with aqueous
10% sodium hydroxide at reflux provided the 3-carbox-
ylic acid derivative 2b, which was transformed into the
benzyl ester 2c by treatment with benzylalcohol and
sodium hydrogencarbonate in anhydrous DMF
(Scheme 3). Following the synthetic route described in
the literature for compounds 2d–k,21 the heating of ester
2a with the appropriate amine in a sealed tube provided
the new carboxamide derivatives 2k–q (Scheme 3). Selec-
tive reduction of the nitro derivative 2q was performed
in glacial acetic acid, in the presence of Pd/C as a cata-
lyst, to give the amino derivative 2r (Scheme 4), which,
by reaction with Ac2O or benzoylchloride, afforded the
imide derivative 2s and the amide derivative 2t, respec-
tively (Scheme 4). The heating of the 7-acetamido-1,8-
naphthyridin-4(1H)-on-3-carboxylic acid ethyl ester
3a22 with p-chlorobenzylamine in a sealed tube provided
the carboxamide derivative 3b. Under these conditions,
also the hydrolysis of the acetamido group takes place
(Scheme 5). As described in Scheme 6, the treatment
of the 7-amino derivative 3c21 with Ac2O afforded the
7-acetamido derivative 3d. Diazotization of compound
3c, carried out in aqueous 96% sulfuric acid at ꢀ12 °C
during the addition of NaNO2, and then at 40 °C for
4 h, gave the 7-hydroxy derivative 3e. On the contrary,
the diazotization of 3c performed in aqueous 37%
hydrochloric acid, or in aqueous 48% hydrobromic acid
at ꢀ5 °C during the addition of NaNO2, and then at
40 °C for 3 h, afforded the 7-chloronaphthyridine 3f or
7-bromonaphthyridine 3g, respectively. Dehalogenation
of 3f was performed with H2 in the presence of Pd/C as a
catalyst to give the derivative 3h. Finally, the reaction of
the 7-chloronaphthyridine 3f with an excess of the
appropriate amine in a sealed tube at 120 °C for 24 h
gave 3i–m (Scheme 6).
The affinities of 1,8-naphthyridine derivatives 1a–
e,f,23h, 2a,c,d–j,21k–t,u–v,21 and 3b–m, were determined
by measuring their ability to displace the specific
binding of the agonists [3H]N6-(cyclohexyl)-adenosine
([3H]CHA) and [3H]2-[[p-(2-carboxyethyl)-phenyl]eth-
yl]amino-50-(N-ethylcarbamoyl)-adenosine ([3H]CGS21
680) from bovine (1a–f,h, 2a,c–v, and 3b–n) and human
(1a–f,h, 2a,c–p,u,v, 3b and 3c) cortical (A1) and striatal
(A2A
)
membranes, respectively.24–27 Moreover, for
some compounds (2d,g,l, and 2o), the affinity at the hu-
man cloned A2B receptor was also determined by mea-
suring their ability to inhibit NECA-mediated cAMP
accumulation.28 Finally, the affinity of only the 1,8-
naphthyridine derivative 2d was determined by measur-
ing its ability to displace the binding of [125I]AB-
MECA from human cloned receptors (A3).13 These
data, plus the receptor affinity for the antagonist 5-
amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,
4-triazolo[1,5-c]pyrimidine (SCH58261), expressed as
inhibition constants (Ki, nM), are summarized in Table
1.
The data show that the new naphthyridine derivatives
generally exhibit a higher affinity for the A2A adenosine
receptor than for the A1 adenosine receptor. The only
exceptions are the 1f, 3i, and 3j derivatives, which dis-
play a modest affinity for the bA1 receptor, and are com-
pletely ineffective towards the bA2A receptor. As regards
the affinity at the hA2BAR and the hA3AR, these com-
pounds present very low inhibition percentages at the
concentration used in the experiments (10 lM for the
A2B receptor and 1 lM for the A3 receptor) with the re-
sult that the corresponding Ki values were not calculat-
ed. Furthermore, the results of the binding studies
indicate that the affinity at the hA1AR is not very differ-
ent from that found at the bA1AR; likewise, the affinity

C. Manera et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4604–4610
4607
Table 1. Affinity of 1,8-naphthyridine derivatives 1a–f,h, 2a,c,d–v, 3b–n in radioligand binding assays at bovine brain A1, A2A, and human brain A1
and A2Areceptorsa,b
Compound
Ki (nM)
R1
R2
bA1
bA2A
hA1
hA2A
1a
1b
1c
Ph
Ph
OH
Cl
>10,000
>10,000
>10,000
>10,000
3360 184
>10,000
>10,000
720 38
>10,000
>10,000
>10,000
4180 217
>10,000
>10,000
8720 470
>10,000
>10,000
4160 220
—
3330 188
>10,000
5360 303
9140 532
>10,000
>10,000
980 51
—
Ph
Ph
N3
SH
3340 179
6330 364
>10,000
1d
1e
Ph
Ph
CyclohexylNH
NHNH2
OH
1f
220 10
8730 450
>10,000
1h
2a
2c
o-ClPh
CH3CH2
PhCH2
PhCH2
CH3
CH3
>10,000
—
—
2d
2e
CH3
CH3
280 11
1740 58
>10,000
50
3
630 30
1630 64
>10,000
>10,000
>10,000
5600 88
>10,000
1650 70
4370 290
1580 117
730 41
300 20
717 37
—
30
150
2
6
p-ClPhCH2
Morph
210 14
8660 440
2868 130
930 50
390 17
1430 70
200 13
740 50
185 11
2f
CH3
CH3
>10,000
2g
2h
2i
N-CH3pipz
Cyclohexyl
4-CH3-cyclohexyl
Isopentyl
p-FPhCH2
p-OCH3PhCH2
p-CH3PhCH2
PhCH2CH2
Furfuryl
PhCH(CH3)
p-NO2PhCH2
p-NH2PhCH2
p-N(COCH3)2PhCH2
p-(NHCOPh)PhCH2
Cyclohexyl
PhCH2
>10,000
>10,000
1750 76
830 47
360 14
640 32
115 12
2405 175
159 100
150 17
CH3
CH3
6000 295
>10,000
2j
CH3
CH3
2k
2l
1770 88
>10,000
CH3
CH3
2m
2n
2o
2p
2q
2r
2230 147
680 25
1350 76
418 20
1634 88
2864 150
>10,000
CH3
CH3
140
45
8
2
6
5
7
35
115
3
8
CH3
CH3
120
99
—
CH3
CH3
146
—
—
—
—
—
2s
1644 85
588 29
>10,000
>10,000
540 37
300 13
6780 355
>10,000
2t
CH3
CH3
7590 410
>10,000
>10,000
—
2u
2v
>10,000
>10,000
6240 341
630 26
—
7140 415
870 50
500 25
CH3
NH2
3b
3c
p-ClPhCH2
PhCH2
PhCH2
4490 240
970 50
>10,000
NH2
160
8
3d
3e
NHCOCH3
OH
Cl
—
PhCH2
PhCH2
>10,000
—
—
—
—
—
—
—
—
—
—
—
3f
586 32
5319 300
2748 135
677 26
977 51
>10,000
67
4
3g
3h
3i
PhCH2
PhCH2
Br
H
3543 158
1169 60
>10,000
—
—
PhCH2
PhCH2
NHCH2Ph
NHCH2CH2Ph
CyclohexylNH
N(CH3)2
N(CH2CH2OH)2
—
—
3j
>10,000
>10,000
3k
3l
PhCH2
PhCH2
PhCH2
—
—
122
6
57
3
3m
SCH58621
>10,000
357 35
>10,000
2.2 0.3
—
463 45
2.5 0.4
a Inhibition of specific [3H]CHA binding to bovine and human brain cortical membranes expressed as Ki SEM (n = 3) in nM.
b Inhibition of specific [3H]CGS21680 binding to bovine and human striatal membranes expressed as Ki SEM (n = 3) in nM.
at the hA2AAR is very similar to that found at the
bA2AAR.
The results obtained indicate that the structural require-
ments for a good affinity at the A2AAR in this series of
naphthyridine derivatives appear to be the presence of a
polar substituent at the position 3 of the heterocyclic
nucleus, instead of a lipophilic group, as confirmed by
the comparison of 1a with 2d. In particular, the presence
of an aromatic carboxamide, such as benzylamide or
furfurylamide, seems to be necessary. Furthermore, the
presence of a methylene spacer between the naphthyri-
dine nucleus and the carboxamide group leads to a
Compounds 2d,o, 3f and 3l show a significant affinity
at the A2AAR, with Ki values in the range of
30.0–67.0 nM, while compounds 2e,k,m,n,p,q, and 2r
display an average A2AAR affinity, with Ki values
in the range of 99.0–300.0 nM. The other compounds
show a
ineffective.
moderate affinity, or are completely

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C. Manera et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4604–4610
marked decrease in the affinity, as can be seen from a
comparison of 2d with 2v. Lastly, in order to obtain a
good affinity at the A2AAR, a lipophilic group, or an ali-
phatic amine without a large steric hindrance, seems to
be necessary at the position 7 of the naphthyridine
nucleus as is clear from a comparison of compound 2d
versus 3e and compound 3l versus 3j.
For each of the considered antagonists 1b,f, 2c,d,h,
3e,f,h, and 3l, the complexes with the bA1AR and the
hA2AAR were optimized through MacroModel31 pro-
gram after a computational procedure of 200 ps of
Molecular Dynamics at 300 °K followed by PR Conju-
gate Gradient (PRCG) minimization, using the Amber32
forcefield with the derivative convergence criterion at a
value of 0.05 kJ/A-mol.
Models of the bA1AR and the hA1AR had been recently
developed through a homology procedure, which used
the bovine rhodopsin as a template;14 specific ligands
were then docked into the models and so obtained com-
plexes were optimized in such a manner they were in
agreement with site-directed mutagenesis data.
The receptor–ligand interaction energies of the opti-
mized complexes were calculated by MacroModel as
the sum of all nonbonded terms of the steric energy
(electrostatic and van der Waals) between the atoms of
the ligand and the atoms of the receptor model.
Subsequently, a molecular model of the hA2AAR was
built29 through a similar procedure but the initial
hA1AR model, the one not completely refined through
MD procedure, was used as a template so that the man-
ual refinement carried out on the A1AR model in order
to adjust the structure on the experimental data of site
directed mutagenesis was identical in both A1AR and
A2AAR. Successively, the structure of the complex with
the specific ligand CGS21680 was optimized, in order to
respect the information given by mutagenesis30a–30f for
agonists and antagonists.
All compounds 1b,f, 2c,d,h, 3e,f,h, and 3l occupied
approximately the same binding site of the bA1AR as
the 1,8-naphthyridine derivatives previously studied,14
also if these first ones arranged deeper into the receptor.
As already reported,14 the binding of the previously
studied 1,8-naphthyridines (and also of other potent
A1AR antagonists like DCPCX), had appeared to occur
in a region between TM3, TM6, and TM7, where a ser-
ies of lipophilic interactions were able to better stabilize
these antagonists in the bA1AR than in the hA1AR. A
graphical comparison between the computational stud-
ies carried out on the already published 1,8-naphthyri-
din-2,4,7-trisubstituted derivatives14 and the new 1,8-
naphthyridines substituted at 3, 4, and 7 positions show
that the increasing of the molecular size provokes a pro-
gressive shift of the ligand towards the TM3 and a loss
of interaction with the residues of the TM6, such as
His251 (see Fig. 1).
The final model of the hA2AAR was used to perform a
manual docking procedure of the compounds 1b,f,
2c,d,h, 3e,f,h, and 3l, availing the arrangement into the
bA1AR of some compounds previously studied,14 consid-
ering all the orientations that allow the interactions sug-
gested by the mutagenesis data as starting points for the
complexes construction. During the MD simulation was
applied distance constraints between the residue Ser94
and the naphthyridine N1, and between His251 and the
oxygen at the position 4 of the ligands, but the constraints
were gradually relaxed during the simulation, and re-
moved in the last step of minimization.
Between the two compounds of type 1, only 1f can inter-
act effectively in the binding site of the bA1AR with
His251 (Fig. 2), because of the hydrazine on the naph-
thyridine core which bends this residue forwards: the li-
gand stretches parallel to TM3, in a narrow longitudinal
cavity delimited by Ile95, Leu98, Phe242, and Trp247,
and as a result naphthyridine N1 can interact with
Ser94 through a hydrogen bond. In the bA1AR, the
binding cavity is smaller because of the presence of the
nonpreserved Pro86 in TM3 and Pro191 in TM5, which
changes the folding of the helices and allows the inter-
helix hydrogen bonding between TM3 and TM5
(Gln92-Trp188 and Gln92-Asn184). In the hA2AAR,
where the two prolines are a valine and a leucine, the
The docking was studied in the hA2AAR because of the
lack of the primary structure of the bA2AAR, that pre-
vents the construction of its molecular model, but the
affinity data for the bA2AAR were used, because they
were more complete and homogeneous; on the other
hand, the available data indicated the same affinity pro-
file of these antagonists in both the bA2AAR and the
hA2AAR.
Figure 1. Docking of the 7-chloro-4-hydroxy-2-phenyl-1,8-naphthyridine previously reported14 (a), compound 1f (b), and compound 2d (c) in the
A1AR.

C. Manera et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4604–4610
4609
Figure 2. Compound 1f docked into the bA1AR (left) and hA2AAR (right) binding site. Interatomic distances in Angstroms between H-bonded
atoms are reported in yellow. The surfaces of the receptors cavities are shown in grey, and TM3 and TM5 backbones are represented through
magenta ribbons.
relative positions of TM3 and TM5 are different and the
cavity is larger, consequently 1f is not parallel to TM3,
and the naphthyridine nucleus shifts toward TM7, with-
out any interaction with Ser94 (see Fig. 2).
that the larger hA2AAR binding cavity allows different
orientations of ligands in this receptor, whereas in the
bA1AR they are generally arranged in the same manner
between TM3 and TM6, shifted towards TM7 and with-
out any interaction with TM5. Among the possible ori-
entations of compounds 1b,f, 2c,d,h, 3e,f,h, and 3l in the
hA2AAR, only 2d, 3f, and 3l, fit into in the crevice,
inserting the naphthyridine nucleus turned towards
TM5, into the lipophilic pocket formed by Trp246
(TM6), Pro189 (TM5), and Ile92 (TM3) and interact
with the residue Asn253 through the amidic group.
The difference in interaction energy between the
bA1AR–1f and the hA2AAR–1f complexes is ꢀ3.8 kcal,
in agreement with the higher stability of the A1 complex.
On the contrary, compound 1b, without any polar sub-
stituent on the naphthyridine is able to form hydrogen
bond, has no activity on the bA1AR or the hA2AAR,
and has a similar docking in the two subtypes, without
any strong interactions with the binding site residues.
Figure 3 shows, as an example, the binding mode of 2d
with the hA2AAR: the presence of the methyl (or N-di-
methyl substituent) on the naphthyridine core raises
the benzylic chain and allows an effective interaction
between Asn253 and the amidic group of the ligand, in
Compounds of types 2 and 3 possess a longer amidic
chain which seems slightly to favor the affinity for the
A2AAR. The docking studies on these compounds show
Figure 3. Comparison between the arrangement of the hA2AAR and bA1AR. Compounds 2d and 3e occupy different lipophilic pockets of the
hA2AAR, due to the variation of the substituent in position 7. In the smaller cavity of the bA1AR, also the compound 2d stretches parallel to TM3
without interactions with TM6.

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13. Ferrarini, P. L.; Mori, C.; Manera, C.; Martinelli, A.;
Mori, F.; Saccomanni, G.; Barili, P. L.; Betti, L.;
Giannaccini, G.; Trincavelli, L.; Lucacchini, A. J. Med.
Chem. 2000, 43, 2814.
addition to the hydrogen bond between Ser94 and naph-
thyridine N1, and a strong lipophilic stabilization
thanks to His250.
14. Ferrarini, P. L.; Betti, L.; Cavallini, T.; Giannaccini, G.;
Lucacchini, A.; Manera, C.; Martinelli, A.; Ortore, S. G.;
Tuccinardi, T. J. Med. Chem. 2004, 47, 3019.
15. Pastorin, G.; Da Ros, T.; Spalluto, G.; Deflorian, F.;
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Compounds such as 3e or 3h, which have smaller sub-
stituents in position 7, do not interact with Asn253,
and shift into a lower lateral lipophilic pocket formed
by Trp246 and Phe242 of TM6, Ile92, Leu96 of TM3;
this is shown in Figure 3 for compound 3e.
In the bA1AR, 2d, like the other compounds 1b,f, 2c,h,
3e,f,h, and 3l, can interact only with Ser94 (see Fig. 3)
and its interaction energy is 3.1 kcal higher than the
A2AAR–2d complex.
17. Kim, Y.-C.; de Zwart, M.; Chang, L.; Moro, S.; von
Kuenzel, J. K.; Melman, N.; IJzerman, Ad P.; Jacobson,
K. A. . J. Med. Chem. 1998, 41, 2835.
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We may thus conclude that the insertion of an amidic
group into the benzylic chain of the naphthyridine fa-
vors the interaction of the ligands with the larger cavity
of the hA2AAR, because of the possibility of a interac-
tion with Asn253. This interaction is favoured if the
substituent in position 7 is quite small and slightly lipo-
philic, such as methyl (2d) or N-dimethyl (3l) with the re-
sult that the antagonist can occupy the crevice delimited
below by Trp246 and above by Asn253.
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Acknowledgment
Financial support from Italian MURST is gratefully
acknowledged.
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