title: Synthesis and biological evaluation of 14-alkoxymorphinans. 17. Highly delta opioid receptor selective 14-alkoxy-substituted indolo- and benzofuromorphinans.
abstract: 14-Alkoxy analogues of naltrindole and naltriben differently substituted in positions 5 and 17 and at the indole nitrogen (compounds 28-44) have been synthesized in an effort to enhance the delta potency and/or delta selectivity and in order to further elaborate on structure-activity relationships of this class of compounds. Introduction of a 14-alkoxy instead of the 14-hydroxy group present in naltrindole resulted in somewhat lower delta binding affinity, while in many cases (compounds 31, 34, 37, 40, 41, 44, HS 378) the delta receptor selectivity was considerably increased. An ethoxy group in position 14 is superior to other alkoxy groups concerning delta affinity and selectivity (34, 41, 42, 44, HS 378). In [35S]GTP gamma S binding, compounds 34, 41, and HS 378 exhibited about one-tenth the antagonist potency of naltrindole at delta opioid receptors while their delta antagonist selectivity was considerably higher. 17-Methyl-substituted compounds 35 and 44 were found to be pure delta receptor agonists in this test.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schütz
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Robert
authors.initials: R
authors.lastname: Horel
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
authors.forename: Martin
authors.initials: M
authors.lastname: Koch
authors.forename: Ruth
authors.initials: R
authors.lastname: Meditz
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Greiner
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidhammer
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D008566:Membranes; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)