A New Structural Motif for μ-Opioid Antagonists

On the basis of the structural features of the Dmt-Tic pharmacophore, a new motif leading to a fairly potent μ-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 constr...

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Veröffentlicht in:	Journal of medicinal chemistry 2005-05, Vol.48 (10), p.3644-3648
Hauptverfasser:	Van den Eynde, Isabelle, Laus, Georges, Schiller, Peter W, Kosson, Piotr, Chung, Nga N, Lipkowski, Andrzej W, Tourwé, Dirk
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Benzazepines - chemical synthesis Benzazepines - chemistry Benzazepines - pharmacology Biological and medical sciences Electric Stimulation Guinea Pigs Ileum - drug effects Ileum - physiology In Vitro Techniques Medical sciences Muscle Contraction Muscle, Smooth - drug effects Muscle, Smooth - physiology Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Propane - analogs & derivatives Propane - chemical synthesis Propane - chemistry Propane - pharmacology Radioligand Assay Receptors, Opioid, mu - antagonists & inhibitors Receptors, Opioid, mu - physiology Stereoisomerism Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	On the basis of the structural features of the Dmt-Tic pharmacophore, a new motif leading to a fairly potent μ-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 μ-opioid receptor. The stereoselective synthesis of four stereoisomers is performed starting from homochiral 2‘,6‘-dimethyltyrosine (Dmt) and o-aminomethylphenylalanine.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm0491795