Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

Abstract

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.

The impact of β‐azido(or 1‐piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues

“…Our results are in agreement with those obtained for dermorphin analogues containing conformationally constrained 4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one (α‐MeAba) in position 3 .…”

“…Because pain relief is mediated mainly through MOR, it is important to understand the interactions between MOR ligands and the receptor. Therefore, hundreds of analogues of the dermorphin and dermorphin‐like peptides have been synthesised .…”

Azepinone-Containing Tetrapeptide Analogues of Melanotropin Lead to Selective hMC4R Agonists and hMC5R Antagonist

“…We concluded, therefore, that preorganization in solution was absent or very limited. In contrast to earlier studies, 25 this result could be explained by the fact that the conformational constraint was each time introduced as the first amino acid of the tetrapeptide sequence ( Figure 2). Peptides 2 and 4 were docked into the active state model of hMC4R proposed by Mosberg et al, 26 which was also used in the docking study of MT-II and SHU-9119 by Grieco and coworkers.…”

Synthesis of Heterocyclic Analogs of α‐aminoadipic Acid and its Esters Based on Imidazo[2,1‐b][1,3]Thiazole

“…In recent years, Schöllkopf's methodology of stereoselective α-amino acid synthesis was applied as an efficient method for the preparation of enantiomerically pure derivatives of aryl amino acids [11], including phenylalanine [12], constrained cyclic quaternary amino acids [13], and (S)-2-amino-8-oxodecanoic acid [14]. Diethyl (Boc-amino)malonate is a precursor used for the preparation of racemic α-amino acids [15].…”

“…of approximately 98% according to the 1 H NMR spectrum of the crude product). The absolute (S)-configuration of the introduced stereo-center was assigned in accordance with the normal findings in Schöllkopf's asymmetric amino acid synthesis [10][11][12][13][14]. It is known that the isopropyl group of the valine residue imposes a strong facial bias by hindering the lower face of almost planar enolate 10, thereby directing the electrophile to the upper face [22].…”