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.