title: Essential structure of opioid κ receptor agonist nalfurafine for binding to κ receptor 1: synthesis of decahydroisoquinoline derivatives and their pharmacologies.
abstract: On the basis of the three-dimensional pharmacophore model of opioid κ agonists, we simplified the structure of nalfurafine (selective κ agonist) to find the essential structural moieties for binding the opioid receptors, especially κ receptor type. As a result, we found that the trans-fused decahydroisoquinoline derivatives without a phenol ring bound the opioid receptor in micromolar order and that both the amide side chain and the nitrogen substituted by the cyclopropylmethyl group were indispensable moieties for eliciting the κ selectivity. The simple decahydroisoquinoline without amide side chain also bound the opioid receptor without receptor type selectivity, suggesting that the message-address concept would be applicable to even these simple derivatives. These findings that the simple decahydroisoquinoline derivatives showed the affinities for the opioid receptors, especially some of the compounds showed κ selectivity, are the first example in the opioid field.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Tokyo 108-8641, Japan. nagaseh@pharm.kitasato-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Satomi
authors.initials: S
authors.lastname: Imaide
authors.forename: Takaaki
authors.initials: T
authors.lastname: Yamada
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hirayama
authors.forename: Toru
authors.initials: T
authors.lastname: Nemoto
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamaotsu
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009019:Morphinans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820