C. M. Park et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3844–3847
3847
Table 3
5-HT2C receptor selectivity profiles over serotonin (5-HT1A–5-HT7) and dopamine (D2–D4) receptor subtypesa
b
Compound
IC50 (nM)
5-HT2C
5-HT1A
5-HT2A
5-HT6
5-HT7
D2
D3
D4
SB-243213
15d
15e
15f
15k
0.7
4.5
10.7
1.9
0.5
1.6
>1000
32.4
667
>1000
>1000
>1000
>1000
>10,000
>10,000
>10,000
>10,000
>10,000
>1000
>10000
>10000
>1000
>1000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
15l
a
Receptors were all cloned human receptors expressed in CHO, HEK293 or SF9 cells, and [3H] radioligands were as follows: 8-OH-DPAT (5-HT1A), ketanserin (5-HT2A),
mesulergine (5-HT2C), LSD (5-HT6, and 5-HT7), and spiperone (D2–D4).
b
IC50 values are means of two or three separate competitive experiments.
A.; Lightowler, S.; Middlemiss, D. N.; Riley, G. R.; Trail, B.; Wood, M. Bioorg.
Med. Chem. Lett. 2000, 10, 1863.
12. Hamprecht, D.; Micheli, F.; Tedesco, G.; Checchia, A.; Donati, D.; Petrone, M.;
Terreni, S.; Wood, M. Bioorg. Med. Chem. Lett. 2007, 17, 428.
13. Hopkins, C. R.; Czekaj, M.; Kaye, S. S.; Gao, Z.; Pribish, J.; Pauls, H.; Liang, G.;
Sides, K.; Cramer, D.; Cairns, J.; Luo, Y.; Lim, H.; Vaz, R.; Rebello, S.; Maignan, S.;
Dupuy, A.; Mathieu, M.; Levell, J. Bioorg. Med. Chem. Lett. 2005, 15, 2734.
14. Cross, P. E.; Dickinson, R. P.; Parry, M. J.; Randall, M. J. J. Med. Chem. 1986, 29,
1637.
possess the excellent 5-HT2C affinity and the selectivity over the 5-
HT2A receptor and other related serotonergic and dopaminergic
receptor subtypes. Additional studies with such compounds are
now in progress.
Supplementary data
15. Terzioglu, N.; Rijn, R. M.; Bakker, R. A.; Esch, I. J. P.; Leurs, R. Bioorg. Med. Chem.
Lett. 2004, 14, 5251.
16. Ohishi, Y.; Mukai, T.; Nagahara, M.; Sajima, M.; Kajikawa, N. Chem. Pharm. Bull.
1989, 37, 2398.
Supplementary data associated with this article can be found, in
17. Landis, P. S.; Brennan, J. A.; Venuto, P. B. J. Chem. Eng. Data 1967, 12, 610.
18. (a) Pazos, A.; Hoyer, D.; Palacios, J. M. Eur. J. Pharmacol. 1985, 106, 539; (b) Park,
W. K.; Jeong, D.; Cho, H.; Lee, S. J.; Cha, M. Y.; Pae, A. N.; Choi, K. I.; Koh, H. Y.;
Kong, J. Y. Pharmacol. Biochem. Behav. 2005, 82, 361; (c) Frozen membranes
from stable CHO-K1 cell line expressing the human recombinant 5-HT2C
receptor was used. For the binding assay, [3H]-mesulergine (1 nM), receptor
membrane and test compounds were added into 50 mM Tris–HCl (pH 7.7)
References and notes
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buffer containing 0.1% ascorbic acid and 10 lM pargyline. The incubations
were performed for 30 min at 37 °C, and these were terminated by rapid
filtration through Whatman GF/C glass fiber filter presoaked in 1% BSA. The
filter was covered with MeltiLex, sealed in a sample bag followed by drying in
the microwave oven, and counted by Microbeta Plus (Wallac, Finland). Non-
specific binding was determined using 0.5 lM mianserin. Competition binding
7. (a) Bromidge, S. M.; Dabbs, S.; Davies, D. T.; Davies, S.; Duckworth, D. M.;
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studies were carried out with 7–8 varied concentrations of the test compounds
run in duplicate tubes, and isotherms from three assays were calculated by
computerized non-linear regression analysis (GraphPad Prism Program, San
Diego, USA) to yield IC50 (nM) values.
19. The compound 15n was described to exhibit inhibitory activity against 5-HT3
receptor in JP 03161470.
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A.; Ruggiero, D. A.; Tamir, H. J. Neurosci. Res. 2000, 61, 674; (b) Cussac, D.;
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HT2C receptors was determined by measuring the [35S]GTP
cS binding. The
assay mixture consists of 20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl2,
1 mM DTT, 1 mM EDTA. Incubation was started by addition of membrane
suspension and test compounds. Following 45 min incubation at 30 °C, bound
10. Hamprecht, D.; Micheli, F.; Tedesco, G.; Donati, D.; Petrone, M.; Terreni, S.;
Wood, M. Bioorg. Med. Chem. Lett. 2007, 17, 424.
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E.; Jones, J.; King, F. D.; Saunders, D. V.; Blackburn, T. P.; Holland, V.; Kennett, G.
[
35S]GTP
cS levels were determined by liquid scintillation counting. A
compound showing P50% inhibitory effects on 5-HT-stimulated [35S]GTP
cS
was classified as an antagonist.