A new structural motif for mu-opioid antagonists.
On the basis of the structural features of the Dmt-Tic pharmacophore, a new motif leading to a fairly potent mu-opioid antagonist is described. This motif contains the 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-one skeleton as a substitute for the Tic residue, which provides the conformational constraint compatible with the mu-opioid receptor. The stereoselective synthesis of four stereoisomers is performed starting from homochiral 2',6'-dimethyltyrosine (Dmt) and o-aminomethylphenylalanine.
Van den Eynde
Isabelle
I
Eenheid Organische Chemie, Vrije Universiteit Brussel, 2, Pleinlaan, B-1050 Brussels, Belgium.
Laus
Georges
G
Schiller
Peter W
PW
Kosson
Piotr
P
Chung
Nga N
NN
Lipkowski
Andrzej W
AW
Tourwé
Dirk
D
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011407:Propane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001552:Benzazepines; D017450:Receptors, Opioid, mu; D011407:Propane