title: Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2: Propellane derivatives with an amide side chain.
abstract: We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo, Japan. nagaseh@pharm.kitasato-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Junko
authors.initials: J
authors.lastname: Akiyama
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakajima
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hirayama
authors.forename: Toru
authors.initials: T
authors.lastname: Nemoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D000577:Amides; D000701:Analgesics, Opioid; D001952:Bridged-Ring Compounds; D017473:Receptors, Opioid, kappa