title: Synthesis of novel diazatricyclodecanes (DTDs). Effects of structural variation at the C3' allyl end and at the phenyl ring of the cinnamyl chain on mu-receptor affinity and opioid antinociception.
abstract: Two series of analogues of 9-propionyl-10-cinnamyl-9,10-diazatricyclo[4.2.1.1(2,5)]decane (1a) and 2-propionyl-7-cinnamyl-2,7-diazatricyclo[4.4.0.0(3,8)]decane (2a), in which the cinnamyl moiety was replaced by various aralkenyl chains, 1b-l and 2b-l, respectively, have been synthesized and evaluated for their ability to bind to the opioid mu-, delta- and kappa-receptors. The binding data indicated that compounds 1b,d,e,h and 2b,d,e,f,h,i showed a mu-affinity in the low nanomolar range with moderate or negligible affinity towards delta- and kappa-receptors. Selected DTDs, the pairs 1,2b, 1,2e and 1,2h, were also evaluated for analgesic effect. In the hot plate test, only 1b given ip was found to have similar opioid antinociception and chronic tolerance as morphine.
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy. pinger@uniss.it
authors.forename: Gérard Aimè
authors.initials: GA
authors.lastname: Pinna
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cignarella
authors.forename: Stefania
authors.initials: S
authors.lastname: Ruiu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Loriga
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.forename: Stefania
authors.initials: S
authors.lastname: Villa
authors.forename: Giuseppe Enrico
authors.initials: GE
authors.lastname: Grella
authors.forename: Gregorio
authors.initials: G
authors.lastname: Cossu
authors.forename: Walter
authors.initials: W
authors.lastname: Fratta
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001391:Azo Compounds / Q000737:chemistry*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002934:Cinnamates / Q000737:chemistry*; D043822:Cyclodecanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D010147:Pain Measurement; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D001391:Azo Compounds; D002934:Cinnamates; D043822:Cyclodecanes; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu