Y. Sugimoto et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3569–3573
3573
Table 4. Effect of heterocycle and amide linkage on central part
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H
N
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(CH2)2
Cl
Me2N
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a
IC50 (nM)
Compound
R
N
O
N
14
600
N
N
18
22
26
29
30
>1000 (39%)
>1000 (46%)
>1000 (37%)
>1000 (18%)
>1000 (41%)
O
N
N
N
N
N
O
O
NH
O
NH CH2
a Binding affinities for the ORL1 receptor. Numbers in parentheses
indicate % inhibition at 1 lM.
this antagonist motif and the SAR resulted in a 2-fold
increase (analog 67) in potency for ORL1 compared to
the prototype compound 33.
Acknowledgment
We thank Dr. Takeshi Sagara for suggestions and
helpful discussions.
References and notes
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18. Synthesized from corresponding terminal olefin in three
steps [(1) MCPBA; (2) NaN3; (3) H2, Pd/C].
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previously: Ozaki, S.; Kawamoto, H.; Itoh, Y.; Miyaji,
M.; Azuma, T.; Ichikawa, D.; Nambu, H.; Iguchi, T.;
Iwasawa, Y.; Ohta, H. Eur. J. Pharmacol. 2000, 402, 45.
21. Synthesized from 5-bromo-2-methyl-1,2,3,4-tetrahydro-
isoquinoline.
5. (a) Bigoni, R.; Giuliani, S.; Calo’, G.; Rizzi, A.; Guerrini,
R.; Salvadori, S.; Regoli, D.; Maggi, C. A. Naunyn
Schmiedebergs Arch. Pharmacol. 1999, 359, 160; (b)
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22. Synthesized from 2-(4-pyridyl)benzaldehyde.
23. Synthesized from 2-chloronicotinaldehyde.
24. Synthesized from 4-bromonicotinaldehyde.