The selective κ opioid receptor agonist nalfurafine was launched in 2009 as an antipruritic drug for patients undergoing hemodialysis.
It is the first clinically used compound with high selectivity for the κ opioid receptor. Nalfurafine had a different pharmacological
feature from other κ opioid agonists. Nalfurafine induced neither addictive nor aversive effects, whereas other κ agonists such as U-
50,488H or salvinorin A produced psychotomimetic effects like dysphoria. Therefore, identification of the essential structural moieties of
nalfurafine for binding to the κ opioid receptor was important for elucidation of the pharmacological discrepancies observed with these κ
opioid agonists. Based on the investigations of various nalfurafine derivatives, the essential structural moieties of nalfurafine were unveiled.
Both the nitrogen substituted by a cyclopropylmethyl group and the 6-amide side chain were indispensable. The phenol ring was
important for obtaining strong binding affinities for the opioid receptors, but not indispensable for exerting selectivity for the κ receptor.
This structure-activity information is expected to lead to the development of novel κ opioid receptor selective agonists.
Keywords: Opioid receptor, κ opioid receptor, agonist, nalfurafine, address part, U-50, 488H, active conformation.
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