title: Conformationally constrained opioid ligands: the Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold.
abstract: Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent mu-selective agonists (Structures 5 and 12) as well as potent and selective delta-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small peptidomimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure-activity data.
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
authors.forename: Debby
authors.initials: D
authors.lastname: Feytens
authors.forename: Rien De
authors.initials: RD
authors.lastname: Wachter
authors.forename: Magali De
authors.initials: MD
authors.lastname: Vlaeminck
authors.forename: Ewa D
authors.initials: ED
authors.lastname: Marczak
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Chris de
authors.initials: Cd
authors.lastname: Graaf
authors.forename: Didier
authors.initials: D
authors.lastname: Rognan
authors.forename: Lucia
authors.initials: L
authors.lastname: Negri
authors.forename: Roberta
authors.initials: R
authors.lastname: Lattanzi
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
mesh_terms: D008024:Ligands; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013237:Stereoisomerism
chemical_list: D008024:Ligands; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu