Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 18 5879
(8) Kourounakis, A. P.; Visser, C.; De Groote, M.; IJzerman, A. P.
Differential effects of the allosteric enhancer (2-amino-4,5-dimethyl-
thienyl)][3-(trifluoromethyl)phenyl]-methanone (PD 81,723) on agonist
and antagonist binding and function at the human wild-type and a
mutant (T277A) adenosine A1 receptor. Biochem. Pharmacol. 2001,
61, 137–144.
General Procedure (B) for the Synthesis of Compounds
7a-l. A solution of piperazine derivative 6a-l (2 mmol) in DMF
(20 mL), containing Et3N (0.3 mL, 2 mmol, 1 equiv), was
hydrogenated over 120 mg of 10% Pd/C at 60 psi for 3 h. The
catalyst was removed by filtration, the filtrate was concentrated to
give residue dissolved with dichloromethane (20 mL), washed with
water (5 mL) and brine (5 mL), and dried (Na2SO4). The solvent
was removed under reduced pressure to obtain a residue purified
by column chromatography.
General Procedure (C) for the Synthesis of Compounds
8a-l. A stirred suspension of thiophene derivatives 7a-l (0.5
mmol) and 100% hydrazine monohydrate (1.2 equiv, 0.6 mmol,
29 µL) in abs ethanol (10 mL) was refluxed for 3 h. After this
time, the resulting solution was left at room temperature for 1 h.
The reaction was finished after the complete solubilization of the
starting material. The solvent was evaporated, and the residue was
portioned between EtOAc (10 mL) and water (5 mL). The separated
organic phase, washed with brine (2 mL) and dried, was then
concentrated under vacuo to obtain a residue that was purified by
column chromatography to give the desired products 8a-l.
(9) (a) Bhattacharya, S.; Linden, J. Effects of long-term treatment with
the allosteric enhancer, PD-81,723, on Chinese hamster ovary cells
expressing recombinant human A 1 adenosine receptors. Mol. Phar-
macol. 1996, 50, 104–111. (b) Bruns, R. F. Conformational induction
versus conformational selection: evidence from allosteric enhancers.
Trends Pharmacol. Sci. 1996, 17, 189–191.
(10) (a) Van der Klein, P. A. M.; Kourounakis, A. P.; IJzerman, A. P.
Allosteric modulation of the adenosine A1 receptor. Synthesis and
biological evaluation of novel 2-amino-3-benzoylthiophenes as allos-
teric enhancers of agonist binding. J. Med. Chem. 1999, 42, 3629–
3635. (b) Baraldi, P. G.; Zaid, A. N.; Lampronti, I.; Fruttarolo, F.;
Pavani, M. G.; Tabrizi, M. A.; Shryock, J. C.; Leung, E.; Romagnoli,
R. Synthesis and biological effects of a new series of 2-amino-3-
benzoylthiophenes as allosteric enhancers of A1-adenosine receptor.
Bioorg. Med. Chem. Lett. 2000, 10, 1953–1957. (c) Tranberg, C. E.;
Zickgraf, A.; Giunta, B. N.; Luetjens, H.; Figler, H.; Murphree, L. J.;
Falke, R.; Fleischer, H.; Linden, J.; Scammells, P. J.; Olsson, R. A.
2-Amino-3-aroyl-4,5-alkylthiophenes: agonist allosteric enhancers at
human A1 adenosine receptors. J. Med. Chem. 2002, 45, 382–389.
(d) Luetjens, H.; Zickgraf, A.; Figler, H.; Linden, J.; Olsson, R. A.;
Scammells, P. J. 2-Amino-3-benzoylthiophene allosteric enhancers of
A1 adenosine agonist binding: new 3,4-, and 5-modifications. J. Med.
Chem. 2003, 46, 1870–1877. (e) Baraldi, P. G.; Romagnoli, R.; Pavani,
M. G.; Nun˜ez, M. C.; Tabrizi, M. A.; Shryock, J. C.; Leung, E.;
Moorman, A. R.; Uluoglu, C.; Iannotta, V.; Merighi, S.; Borea, P. A.
Synthesis and biological effects of novel 2-amino-3-naphthoylth-
iophenes as allosteric enhancers of the A1 adenosine receptor. J. Med.
Chem. 2003, 46, 794–809. (f) Baraldi, P. G.; Pavani, M. G.; Shryock,
J. C.; Moorman, A. R.; Iannotta, V.; Borea, P. A.; Romagnoli, R.
Synthesis of 2-amino-3-heteroaroylthiophenes and evaluation of their
activity as potential allosteric enhancers at the human A1 receptor.
Eur. J. Med. Chem. 2004, 39, 855–865. (g) Baraldi, P. G.; Iaconinoto,
M. A.; Moorman, A. R.; Carrion, M. D.; Cara, C. L.; Preti, D.; Lo´pez,
O. C.; Fruttarolo, F.; Tabrizi, M. A.; Romagnoli, R. Allosteric
enhancers for A1 adenosine receptor. Mini-ReV. Med. Chem. 2007, 7,
559–569.
Acknowledgment. We thank King Pharmaceuticals for
support of this research.
Supporting Information Available: Detailed biological proto-
cols, synthesis and spectroscopic data for compounds 2-5 and
6-8a,l, elemental analyses of compounds 8a-l. This material is
References
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(11) In our experiments, the reference compound PD 81,723 (at a
concentration of 10 µM) did not inhibit [3H]DPCPX binding to human
A1 receptors transfected in CHO cells. For the same reference
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only of 42 ( 7% when tested at 100 µM. We speculate that species
differences in affinity binding of PD 81,723 may explain the
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JM800586P
Romagnoli, Romeo
