Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring.

A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist 5 and their agonist activities against orexin receptors were evaluated. The introduction of N-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of 6 revealed that (-)-6 having a (S)-1-amino-tetralin skeleton showed a OXR selective agonist activity (EC = 2.69 nM for OXR, OXR/OXR = 461) yet its enantiomer (R)-(+)-6 showed a potent OXR dual agonist activity (EC = 13.5 nM for OXR, 0.579 nM for OXR, OXR/OXR = 23.3). These results suggested that upward orientation of the amide side chain against the tetralin scaffold (S-configuration) would be selective for OXR activation, and the downward orientation (R-configuration) would be significant for dual agonist activity. To our best knowledge, there have been no reports thus far that the stereochemistry of one carbon center on the agonist structure regulates the orexin receptor selectivity. Our results would provide important information for the development of OXR selective agonists.