title: The most effective influence of 17-(3-ethoxypropyl) substituent on the binding affinity and the agonistic activity in KNT-127 derivatives, δ opioid receptor agonists.
abstract: We investigated the structure-activity relationship of KNT-127 (opioid δ agonist) derivatives with various 17-substituents which are different in length and size. The 17-substituent in KNT-127 derivatives exerted a great influence on the affinity and agonistic activity for the δ receptor. While the compounds with electron-donating 17-substituents showed higher affinities for the δ receptor than those with electron-withdrawing groups, KNT-127 derivatives with 17-fluoroalkyl groups (the high electron-withdrawing groups) showed high selectivities for the δ receptor among evaluated compounds. In addition, the basicity of nitrogen as well as the structure of the 17-N substituent such as the length and configuration at an asymmetric carbon atom contributed to agonist properties for the δ receptor. Thus, the analog with a 17-(3-ethoxypropyl) group showed the best selectively and potent agonistic activity for the δ receptor among KNT-127 derivatives. These findings should be useful for designing novel δ selective agonists.
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: Yoshihiro
authors.initials: Y
authors.lastname: Ida
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Iihara
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakajima
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: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C555233:KNT 127; D009019:Morphinans; D017465:Receptors, Opioid, delta
keywords: 17-Substituent; CPM; Morphinan; Opioid; cyclopropylmethyl; δ Agonist