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177
Individually, the new compound 6 presents the highest
affinity for a1A and D2 receptors, having a pA2 of 9.07
and a pKi of 7.93, and the second highest in affinity for
5-HT2A receptors (pKi=6.76). Structurally, it possesses
a methyl group in position 4 of coumarin and an
o-methoxyphenyl ring at the piperazine. The substitu-
tion of the 4-methyl group of coumarin by a 4-methoxyl
(7) produced a decrease in the affinity for the three
receptors, this being more pronounced for 5-HT2A
receptors, although both molecules exhibited greater
affinity for the a1A receptors than haloperidol (7.76).
Blakeman, K.; Ahlenius, S.; Svensson, T. H. J. Neural. Trasm.
2000, 107, 1229.
7. Glennon, R. A.; Naiman, N. A.; Lyon, R. A.; Tieteler, M.
J. Med. Chem. 1988, 31, 1968.
8. Martin, E. G.; Elgin, R. J., Jr.; Mathiasen, J. R.; Davis,
C. B.; Kesslick, J. M.; Baldy, W. J.; Shank, R. P.; Di Stefano,
D. L.; Fedde, C. L.; Scott, M. K. J. Med. Chem. 1989, 32,
1052.
9. Marchais, S.; Nowicki, B.; Wikstrom, H.; Brennum, L. T.;
Halldin, C.; Pike, V. W. Bioorg. Med. Chem. 2001, 9, 695.
10. Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.;
Tortorella, V. J. Med. Chem. 1999, 42, 490.
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T.; Nakagawa, K. Chem. Pharm. Bull. 1988, 36, 4377.
12. Mizuno, A.; Ogata, A.; Kamei, T.; Shibata, M.; Shima-
moto, T.; Hayashi, Y.; Nakanishi, K.; Takiguchi, C.; Oka, N.;
Inomata, N. Chem. Pharm. Bull. 2000, 48, 623.
The suppression of the o-methoxy group from the
phenyl piperazine (4 and 5) again gave rise to a reduc-
tion in the affinity for the three receptors that, as
observed in compounds 6 and 7, was much lower if the
4-methyl of the coumarin moiety (4) was substituted by
a 4-methoxyl group (5).
13. Jaen, J. C.; Wise, L. D.; Heffner, T. G.; Pugsley, T. A.;
Meltzer, L. T. J. Med. Chem. 1991, 34, 248.
14. Santana, L.; Teran, C.; Uriarte, E.; Fall, Y.; Unelius, L.;
Tolf, B.-R. Bioorg. Med. Chem. Lett. 1998, 8, 3567.
15. Mokrosz, M. J.; Kowalski, P.; Kowalska, T.; Majka, Z.;
Duszynska, B.; Bojarski, A. J.; Fruzinski, A.; Karolak-Woj-
ciechowska, J.; Wesolowska, A.; Klodzinska, A.; Tatarzynska,
E.; Chojnacka-Wojcik, E. Arch. Pharm. (Weinheim) 1999,
332, 373.
16. Giannangeli, M.; Cazolla, N.; Luparini, M. R.; Magnani,
M.; Mabilia, G. P.; Tomaselli, M.; Baiocchi, L. J. Med. Chem.
1999, 42, 336.
17. Lopez-Rodrıguez, M. L.; Morcillo, M. J.; Fernandez, E.;
Rosado, M. L.; Pardo, L.; Schaper, K.-J. J. Med. Chem. 2001,
44, 198.
18. Barbaro, R.; Betti, L.; Botta, M.; Corelli, F.; Giannaccini,
G.; Maccari, L.; Manetti, F.; Strappaghetti, G.; Corsano, S.
J. Med. Chem. 2001, 44, 2118.
The substitution of the N4-phenyl by a pyrimidine or
pyridine group (compounds 8–11) produces a decrease
in the affinity for a1A and D2 receptors. Moreover,
unlike what occurred with the previous compounds
(4–7), the presence of a methoxyl group at position 4 of
coumarin nucleus did not diminish the affinity for the
receptors studied, in fact in some cases a small increase
or no change was observed.
The results suggest that the affinity for the three types of
receptors studied depends on the substitution on the
piperazine N4(o-methoxyphenyl>phenyl>pyrimidine>
pyridine) and to a lesser extent on the substituent at
position 4 of coumarin nucleus, especially for 5-HT2A
receptors.
19. Barbaro, R.; Betti, L.; Botta, M.; Corelli, F.; Giannaccini,
G.; Maccari, L.; Manetti, F.; Strappaghetti, G.; Corsano, S.
Bioorg. Med. Chem. 2002, 10, 361.
20. Compound 5: Yield 65%; mp 139–141 ꢂC. 1H NMR
(CDCl3), d: 7.67 (d, 1H, H-5, J=8.75 Hz), 7.26 (m, 2H, m-),
6.85 (m, 5H, o-, p-, H-6, H-8), 5.55 (s, 1H, H-3), 4.09 (t, 2H,
CH2O, J=6.25 Hz), 3.95 (s, 3H, OCH3), 3.20 (m, 4H,
N4(CH2)2), 2.59 (m, 6H, (CH2)2N1CH2), 2.04 (m, 2H,
CH2CH2CH2). 13C NMR (CDCl3), d: 167.23, 163.80, 163.07,
155.50, 151.70, 129.49, 124.42, 120.08, 116.44, 112.86, 109.22,
101.47, 87.98, 67.18, 56.60, 55.32, 53.70, 49.55, 26.93. FAB-
MS: m/z=395 (M+1, 100%). Anal. calcd for C23H26N2O4
(394.47): C 70.03, H 6.64, N 7.10. Found: C 70.15, H 6.59, N
7.24.
Acknowledgements
The authors are grateful to the Spanish Ministry of Edu-
cation and Culture (PM99-0125), Xunta de Galicia
(PR405A2001/65-0, PGIDT01PXI20303PR, PGIDT00P-
XI20310PR) and Fundacio La Marato de TV3 for finan-
cial support. J.C.G. thanks the University of Santiago de
Compostela for the grant awarded. G.Y.M. is thankful
for the pre-doc grants, from the AECI (Asociacion
Espanola de Cooperacion Internacional) and the Uni-
versity of Santiago de Compostela, and M.E.R. for the
pre-doc grant from the Xunta de Galicia and post-doc
grant from the University of Santiago de Compostela.
Compound 6: Yield 68%; mp 133–134 ꢂC. H NMR (CDCl3),
1
d: 7.48 (d, 1H, H-5, J=8.70 Hz), 6.95 (m, 4H, Ph), 6.86 (dd,
1H, H-6, J=8.80, 2.60 Hz), 6.82 (d, 1H, H-8, J=2.60 Hz), 6.11
(s, 1H, H-3), 4.10 (t, 2H, CH2O, J=6.30 Hz), 3.86 (s, 3H,
OCH3), 3.10 (m, 4H, N4(CH2)2), 2.69 (m, 4H, (CH2)2N1), 2.60
(m, 2H, N1CH2), 2.38 (s, 3H, CH3), 2.04 (m, 2H,
CH2CH2CH2). 13C NMR (CDCl3), d: 162.53, 161.69, 155.70,
152.91, 152.69, 141.74, 125.87, 123.30, 121.40, 118.62, 113.90,
113.02, 112.28, 111.63, 101.87, 67.29, 55.76, 55.40, 53.91,
51.06, 26.94, 19.04. FAB-MS: m/z=409 (M+1, 100%). Anal.
calcd for C24H28N2O4 (408.49): C 70.57, H 6.91, N 6.86.
Found: C 70.26, H 7.07, N 6.80.
Compound 7: Yield 70%; mp 125–128 ꢂC. 1H NMR (CDCl3), d:
7.68 (d, 1H, H-5, J=8.70 Hz), 6.95 (m, 4H, Ph), 6.83 (dd, 1H, H-
6, J=8.70, 2.30 Hz), 6.79 (d, 1H, H-8, J=2.30 Hz), 5.54 (s, 1H,
H-3), 4.10 (t, 2H, CH2O, J=6.30 Hz), 3.95 (s, 3H, OCH3), 3.85
(s, 3H, OCH3), 3.10 (m, 4H, N4(CH2)2), 2.67 (m, 4H, (CH2)2N1),
2.58 (t, 2H, N1CH2), 2.07–1.98 (m, 2H, CH2CH2CH2). 13C
NMR (CDCl3), d: 167.24, 163.80, 163.10, 155.50, 152.69, 141.74,
124.39, 123.29, 121.40, 118.61, 112.90, 111.63, 109.18, 101.46,
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