title: Essential structure of the κ opioid receptor agonist nalfurafine for binding to the κ receptor.
abstract: 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.
authors: Hiroshi
authors: H
authors: Nagase
authors: School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo, Japan. nagaseh@pharm.kitasato-u.ac.jp.
authors: Hideaki
authors: H
authors: Fujii
mesh_terms: D006801:Humans; D009019:Morphinans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820