Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25 7921
Scheme 1a
a Reagents: (A) NaOH; (B) ethanol, concd H2SO4; (C) borane methyl sulfide complex; (D) Jones’s reagent; (E) silica gel column
chromatography.
Scheme 2a
a Reagents: (A) 1,1′-carbonyldiimidazole or 1.2% NaOH or methyl chloroformate.
agonist. Also for this group of compounds, the intrinsic
activities depended on the nature of the arylcarbox-
amide moiety. However, the structural features of the
carboxamide moiety that are responsible of receptor
activation are not clear. From the comparison of activity
data, it could be hypothesized that compounds 1a-6a
interacted with dopamine D3 receptor in a slightly
different manner as did 1b-6b.
the arylcarboxamide moiety of this class of compounds
on intrinsic activity.
Supporting Information Available: Physical and spec-
tral data of all the synthesized compounds, experimental
procedures for synthesis, and biological evaluation. This
material is available free of charge via the Internet at http://
pubs.acs.org.
The antagonists 1a, 2a,b, 3a,b, 5b, trans-6a,b inhib-
ited quinpirole-stimulated Eu-GTP binding with poten-
cies similar to those found in radioligand-binding ex-
periments. On the other hand, the potencies of the
agonists and partial agonists 1b, 4a,b, 5a, cis-6a,b were
slightly different from those found in radioligand-
binding experiments. This might be due to the different
[receptor]/[G-protein] ratio in the membrane prepara-
tions used for the experiments.22
The intrinsic activities of compounds 1a, 2b, and 3b
were assessed by other authors using a mitogenesis
assay measuring the rate of [3H]thymidine incorpora-
tion. Compound 1a10 was reported as an antagonist, and
compounds 2b13 and 3b14 as partial agonists. As men-
tioned above, we have found that compounds 1a, 2b,
and 3b acted as antagonists in the Eu-GTP binding
assay. Therefore, compounds 2b and 3b showed differ-
ent behavior in these two assays. It is noteworthy that
our intrinsic activity data of compound 2b are in
agreement with those published by Garcia-Ladona that
tested such compound in the GTPγS binding assay.17
The source of these differences is probably relates to the
fact that mitogenesis measures a response that is distal
to agonist-induced receptor/G-protein conformational
changes.
References
(1) Levant, B. The D3 dopamine receptor: neurobiology and poten-
tial clinical relevance. Pharmacol. Rev. 1997, 49, 231-252.
(2) Biglan, K. M.; Holloway, R. G. A review of pramipexole and its
clinical utility in Parkinson’s disease. Expert Opin. Pharmaco-
ther. 2002, 3, 197-210.
(3) Sokoloff, P.; Giros, B.; Martres, M. P.; Bouthenet, M. L.; Schwarz,
J. C. Molecular cloning and characterization of a novel dopamine
receptor (D3) as a target of neuroleptics. Nature 1990, 347, 72-
76.
(4) Heidbreder, C. A.; Gardner, E. L.; Xi, Z.-X.; Thanos, P. K.;
Mugnaini, M.; Hagan, J. J.; Ashby, C. R. The role of central
dopamine D3 receptors in drug addiction: a review of pharma-
cological evidence. Brain Res. Rev. 2005, 49, 77-105.
(5) Beardsley, P. M.; Sokoloff, P.; Balster, R. L.; Schwartz, J. C. The
D3R partial agonist, BP 897, attenuates the discriminative
stimulus effects of cocaine and D-amphetamine and is not self-
administered. Behav. Pharmacol. 2001, 12, 1-11.
(6) Pilla, M.; Perachon, S.; Sautel, F.; Garrido, F.; Mann, A.;
Wermuth, C. G.; Schwartz, J. C.; Everitt, B. J.; Sokoloff, P.
Selective inhibition of cocaine-seeking behavior by a partial
dopamine D3 receptor agonist. Nature 1999, 400, 371-375.
(7) Luedtke, R. R.; Mach, R. H. Progress in developing D3 dopamine
receptor ligands as potential therapeutic agents for neurological
and neuropsychiatric disorders. Curr. Pharm. Des. 2003, 9, 643-
671.
(8) Hackling, A. E.; Stark, H. Dopamine D3 receptor ligands with
antagonistic properties. ChemBioChem 2002, 3, 946-961.
(9) Leopoldo, M.; Berardi, F.; Colabufo, N. A.; De Giorgio, P.;
Lacivita, E.; Perrone, R.; Tortorella, V. Structure-affinity rela-
tionship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarbox-
amides as potent and selective dopamine D3 receptor ligands.
J. Med. Chem. 2002, 45, 5727-5735.
(10) Yuan, J.; Chen, X.; Brodbeck, R.; Primus, R.; Braun, J.; Wasley,
J. W. F.; Thurkauf, A. NGB 2904 and NGB 2849: two highly
selective dopamine D3 receptor antagonists. Bioorg. Med. Chem.
Lett. 1998, 8, 2715-2718.
(11) Robarge, M. J.; Husbands, S. M.; Kieltyka, A.; Brodbeck, R.;
Thurkauf, A.; Newman, A. H. Design and synthesis of [(2,3-
dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as novel
ligands selective for the dopamine D3 receptor subtype. J. Med.
Chem. 2001, 44, 3175-3186.
The results presented herein show that structural
modifications of the arylcarboxamide part of N-[4-(4-
arylpiperazin-1-yl)butyl]arylcarboxamide framework in-
fluence the intrinsic activity at D3 receptor in either
1-(2,3-dichlorophenyl) and 1-(2-methoxyphenyl)pipera-
zine derivatives. A wide range of intrinsic activity can
be observed by varying the arylcarboxamide moiety. The
synthesis of a wider number of derivatives becomes
necessary for the full elucidation of the role played by
(12) Campiani, G.; Butini, S.; Trotta, F.; Fattorusso, C.; Catalanotti,
B.; Aiello, F.; Gemma, S.; Nacci, V.; Novellino, E.; Stark, J. A.;
Cagnotto, A.; Fumagalli, E.; Carnovali, F.; Cervo, L.; Mennini,