2454
M. B. Isaac et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2451–2454
Table 5. Receptor binding profile of compound 21
In conclusion, a novel series of potent and selective 5-
HT7 receptor ligands has been discovered. Compound
21 was the most potent in this series and has demon-
strated good in vitro receptor selectivity, thus making it
a valuable tool with which to further characterize the
distribution and function of 5-HT7 receptors in native
tissue and to elucidate their potential role in disease
states. Compound 21 will be further evaluated for its
functional activity at this receptor.
Receptor % Inhibition @ 1 mM Receptor % Inhibition @ 1 mM
5-HT1A
5-HT1B
5-HT1D
5-HT1F
5-HT2A
5-HT2C
5-HT6
1
0
0
5-HT7
M1+M2
D1
D2
D3
3a
35
2
15
27
4
0
20
26
4066a
D4
D5
17
aKi values in nM (see ref 14).
References and Notes
1. Barnes, N.; Sharp, T. Neuropharmacology 1999, 38, 1083.
2. Plassat, J.; Amlaiky, N.; Hen, R. Mol. Pharmacol. 1993, 44,
229.
3. Lovenberg, T.; Baron, B.; De Lecea, L.; Miller, J.; Prosser,
R.; Rea, M.; Foye, P.; Racke, M.; Slone, A.; Siegel, B.;
Danielson, P.; Sutcliffe, J.; Erlander, M. Neuron 1993, 11, 449.
4. Tsou, A.; Kosaka, A.; Bach, C.; Zuppan, P.; Yee, C.; Tom,
L. J. Neurochem. 1994, 63, 456.
5. Bard, J.; Zgombick, J.; Adham, N.; Vaysse, P.; Branchek,
T.; Weinshank, R. J. Biol. Chem. 1993, 268, 23422.
6. Shen, Y.; Monsma, F.; Metcalfe, A.; Jose, P.; Hamblin, M.;
Sibley, D. J. Biol. Chem. 1993, 268, 18200.
Figure 2. Potent 6,7-bicyclohomopiperazine analogues.
7. Ruat, M.; Traiffort, E.; Leurs, R.; Tarddivel-Lacombe, J.;
Diaz, J.; Arrang, J.; Schwartz, J. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 8547.
8. Terron, J.; Falcon-Neri, A. Br. J. Pharmacol. 1999, 127, 609.
9. Linnanen, T.; Brisander, M.; Unelius, L.; Rosqvist, S.;
Nordvall, G.; Hacksell, U.; Johansson, A. J. Med. Chem.
2001, 44, 1337.
10. Forbes, I.; Dabbs, S.; Duckworth, D.; Jennings, A.; King,
F.; Lovell, P.; Brown, A.; Collin, L.; Hagan, J.; Middlemiss,
D.; Riley, G.; Thomas, D.; Upton, N. J. Med. Chem. 1998, 41,
655.
11. Kikuchi, C.; Nagaso, H.; Hiranuma, T.; Koyama, M. J.
Med. Chem. 1999, 42, 533.
12. Lovell, P.; Bromidge, S; Dabbs, S; Duckworth, D; Forbes,
I.; Jennings, A; King, F.; Middlemiss, D.; Rahman, S.; Saun-
ders, D.; Collin, L.; Hagan, J.; Riley, G.; Thomas, D. J. Med.
Chem. 2000, 43, 342.
13. Poss, M.; Purandare, A.; Mattson, R.; Sun, L. (Bristol-
Myers Squibb Co.) Patent WO-00185701, 2001.
14. Ki values in nM are given as the mean of at least two
independent determinations performed in triplicate with less
than 15% deviation.
15. 1HNMR (CDCl3) for compound 21 (a yellow oil): d 7.51
(s, 1H), 7.46 (d, 1H), 7.18 (d, 1H), 7.13 (d, 1H), 6.46 (d,1H),
4.13 (t, 2H), 2.88 (t, 2H), 2.83–1.16 (m, 17H).
led to 51 and 53 with Kis 9 and 10 nM, respectively
(Table 4). On the contrary, the corresponding N-neo-
pentyl (50) and N-phenyl (55) analogue reduced 5-HT7
receptor affinity.
The information gleaned from the N-methylhomopi-
perazinylethyl indole derivatives and the finding that
6,7-bicyclohomopiperazine 21 was very potent promp-
ted us to synthesize and evaluate the affinity of the 6-
chloro (56) and 6-trifluoromethyl (57) analogues of 21.
Both compound were found to be highly potent 5-HT7
receptor ligands (56, Ki=10 nM and 57, Ki=7 nM,
respectively, Fig. 2).
For the most potent compound 2115 (Ki=3 nM), the
binding affinities at other serotonin receptors, dopamine
receptors and muscarinic receptors were measured
(Table 5). It can be seen that 21 possesses very good
selectivity over the battery of receptors examined.