Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies

Nalfurafine, a κ-selective
opioid receptor agonist, unexpectedly
showed a selective antagonist activity toward the orexin 1 receptor
(OX1R) (Ki = 250 nM). Modification
of the 17-amino side chain of the opioid ligand to an arylsulfonyl
group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led
to compound 71 with improvement of the antagonist activity
(OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid
receptor. The dihydrosulfate salt of 71, freely soluble
in water, attenuated the physical dependence of morphine. Furthermore,
all of the active nalfurafine derivatives in this study had almost
no activity for OX2R, which led to high OX1R
selectivity. These results suggest that nalfurafine derivatives could
be a useful series of lead compounds to develop highly selective OX1R antagonists.