No abstract

A series of 4‐amino‐tetrahydro‐2‐benzazepin‐3‐one derivatives (Ac–Aba–Xxx–NHMe) were prepared as tetrapeptide mimetics. Considering the structural resemblance with the so‐called Freidinger lactams, their propensity to adopt a β‐turn conformation was investigated by NMR spectroscopy (solvent and temperature dependence) and molecular modeling. Interestingly, most of these lactams adopt extended conformations, only the spiro‐benzazepinone 9 has a strong preference for the formation of a β‐turn. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

No 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 μ-selective agonists (Structures 5 and 12) as well as potent and selective δ-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,Ndimethylation 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.Conformationally constrained amino acids have found widespread application in search of novel peptidic opioid ligands with minored side-effects. 1-8 Such residues, inducing enhanced receptor selectivity and affinity, can be subdivided in sterically (e.g., β-methylphenylalanine, β-methyltryptophan, β-methyl-2′,6′-dimethyltyrosine) and covalently constrained derivatives [e.g., 2-aminotetralin-2-carboxylic acid (Atc), 2-aminoindane-2-carboxylic acid (Aic), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic)]. 9 The Dmt-Tic scaffold 1, in particular, has been recognized as a firmly established template for opioid ligand design. 3,4 Subtle changes in this scaffold have induced remarkable alterations in opioid receptor selectivity and/or activity, such as enhanced agonism, antagonism, or the acquisition of mixed activities at the opioid subtype receptors (i.e., μ, δ and κ receptors). Replacement of tyrosine by Dmt (2′,6′-

Dermorphin analogues, containing a (S)- and (R)-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the α-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-α-Me-o-cyanophenylalanine precursor for (S)-α-MeAba in acceptable enantiomeric purity. However, by using a Schöllkopf chiral auxiliary, this intermediate was obtained in 88 % ee. [(S)-Aba 3-Gly 4]dermorphin retained μ-opioid affinity but displayed an increased δ-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-α-MeAba 3-Gly 4]dermorphin isomer was more potent than its S epimer. Tar-MD simulations of both non-methylated [Aba 3-Gly 4]dermorphin analogues showed a degree of folding at the C-terminal residues toward the N terminus of the peptide, without however, adopting a stabilized β-turn conformation. The α-methylated analogues, on the other hand, exhibited a type I/I' β-turn conformation over the α-MeAba 3 and Gly 4 residues, which was stabilized by a hydrogen bond involving Tyr 5-HN and D-Ala 2-CO.