Abstract
Nalfurafine hydrochloride (1) was launched on March of 2009 in Japan as the first in class non-narcotic opioid drug for intractable itch caused by haemodialysis. Rational medicinal chemistry effort led us to obtain the morphinan derivative, which is a new chemical class of opioid κ-agonist without the [N-C-C-N(sp2)] pharmacophore sequence of the typical U-50488H derivatives. The applicability of “Message-Address Concept” and “Accessory Site Hypothesis” in the development of the opioid κ-agonist could also be proven. Nalfurafine hydrochloride (1) showed significant opioid κ-agonist activity and induced neither aversion nor preference in rats on the CPP (Conditioned Place Preference) test. No dependence sign was observed in monkey on the self-administration test. This compound was approved without legal narcotic nor psychotropic drug control after a clinical evaluation on human. Details on design rationale and medicinal chemistry of this novel drug will be discussed.
