A New Structural Motif for μ-Opioid Antagonists

Abstract

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.

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

“…24 The opioid subunit in 4 is derived from the μ opioid receptor lead peptide Dmt-D-Arg-Phe-Lys-NH 2 ([Dmt 1 ]DALDA) 5 , 25 and contains a constrained Aba (4- a mino-2- b enz a zepinone) 26-28 moiety in position 3. As this conformationally constrained amino acid was also the core structure of a newly developed NK1 antagonist, 24 Ac- Aba -Gly- N Me-3’,5’-(CF 3 ) 2 -Bn ( 6 ) (corresponding to the blue part in structure 4 , Figure 1), the combination of both ligands led to the hybrid structure Dmt-D-Arg- Aba -Gly- N Me-3’,5’-(CF 3 ) 2 -Bn 4 , a DML with overlapping pharmacophores.…”

Synthesis and Evaluation of the β‐Turn Properties of 4‐Amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐ones and of Their Spirocyclic Derivative

“…[10;11] The 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) skeleton has been applied successfully to constrain a Phe or Tyr side chain in biologically active peptides. [12][13][14][15][16][17][18][19][20] Considering their structural resemblance with dehydroFreidinger lactams 4, we have investigated their potential for adopting turn conformations.…”

“…ium bromide, resulting in the alkylated compound 12 (Figure 2). Hydrolysis of the benzophenone imine 12 using aqueous citric acid provides (S)-o-CN-Phe-OtBu (13). At first a liquid/liquid phase-transfer alkylation of 10 (50 % aq.…”

[d-1-Nal4]endomorphin-2 is a potent μ-opioid receptor antagonist in the aequorin luminescence-based calcium assay

“…A new motif for the μ-opioid antagonists has recently been Life Sciences 79 (2006) 1094 -1099 www.elsevier.com/locate/lifescie developed on the basis of the structural features of the Dmt-Tic pharmacophore. 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 ( Van den Eynde et al, 2005). However, the most selective μ-antagonist peptides known so far are still somatostatin-derived cyclic analogues (CTP, CTOP and CTAP) designed almost 20 years ago (Pelton et al, 1986;Kazmierski et al, 1988;Kramer et al, 1989).…”