Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591836 | Bioorganic & Medicinal Chemistry Letters | 2014 | 4 Pages |
Abstract
Indolopropellane 2 was reported to show almost no binding affinity to the δ opioid receptor (DOR) in spite of the fact that 2 has both the propellane fundamental skeleton (message part) with binding ability to the opioid receptors and a possible DOR address structure (indole moiety). We developed the working hypothesis that almost no binding affinity of 2 to the DOR would be derived from its possibly stable bent conformer. To enable the propellane skeleton to adopt an extended conformation which would reasonably interact with the DOR, quinolinopropellanes 3a-d were designed which had an additional pharmacophore, quinoline nitrogen. The calculated binding free energies of ligand-DOR complexes strongly supported our working hypothesis. The synthesized quinolinopropellane 3a was a selective DOR full agonist, confirming our working hypothesis and the results of in silico investigation.
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Authors
Hiroshi Nagase, Ryo Nakajima, Naoshi Yamamoto, Shigeto Hirayama, Takashi Iwai, Toru Nemoto, Hiroaki Gouda, Shuichi Hirono, Hideaki Fujii,