title: The effect of 17-N substituents on the activity of the opioid κ receptor in nalfurafine derivatives.
abstract: We have previously reported the essential structure of the opioid κ receptor agonist nalfurafine hydrochloride (TRK-820) for binding to the κ receptor. In the course of this study, we focused on the effect of the substituent at 17-N in nalfurafine on the binding affinity for the κ receptor. The exchange of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups, which are strong electron withdrawing substituents, almost completely diminished the binding affinities for the μ and δ opioid receptors, but the binding affinity for the κ receptor was still maintained. As a result, nalfurafine derivatives with 17-fluoro-substituted alkyl groups showed higher selectivities for the κ receptor than did nalfurafine itself. With regard to the κ agonistic activities, the conversion of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups led to the gradual decrease of the agonistic activities in the order corresponding to their binding affinities for the κ receptor. In contrast, the derivative with the bulky 17-isobutyl group showed lower affinity and agonistic activity for the κ receptor than the derivatives with the smaller functional groups. This research suggested that both the electronic property and the steric characteristics of the 17-N substituent would have a great influence on the binding property for the κ receptor.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nemoto
authors.forename: Naoshi
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Naohisa
authors.initials: N
authors.lastname: Wada
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Harada
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tomatsu
authors.forename: Marina
authors.initials: M
authors.lastname: Ishihara
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hirayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwai
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
mesh_terms: D004399:Dynorphins / Q000737:chemistry; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry; D011485:Protein Binding; D017465:Receptors, Opioid, delta / Q000737:chemistry / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000737:chemistry / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D009019:Morphinans; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; C111212:TRK 820; D004399:Dynorphins; D009584:Nitrogen