Conformationally constrained opioid ligands: the Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold.
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.
Ballet
Steven
S
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
Feytens
Debby
D
Wachter
Rien De
RD
Vlaeminck
Magali De
MD
Marczak
Ewa D
ED
Salvadori
Severo
S
Graaf
Chris de
Cd
Rognan
Didier
D
Negri
Lucia
L
Lattanzi
Roberta
R
Lazarus
Lawrence H
LH
Tourwé
Dirk
D
Balboni
Gianfranco
G
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
D008024:Ligands; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu