β 2 - Homo -Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 10
• Main Authors: Tymecka, Dagmara, Lipiński, Piotr F J, Kosson, Piotr, Misicka, Aleksandra
• Format: Journal Article
• Language: English
• Published: Switzerland 25.05.2020
• Subjects: Amino Acids - chemistry; Amino Acids - metabolism; Animals; Aspartic Acid - chemistry; Aspartic Acid - metabolism; Binding Sites; Humans; Ligands; Molecular Docking Simulation; Oligopeptides - blood; Oligopeptides - chemistry; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Stability; Receptors, Opioid, delta - chemistry; Receptors, Opioid, delta - metabolism; Receptors, Opioid, mu - chemistry; Receptors, Opioid, mu - metabolism; Stereoisomerism; β2-Homo-amino acids; opioid peptides; TAPP; µ-opioid receptor; racemic synthesis of β2-amino acids; β2-amino acids
• ISSN: 1420-3049

TAPP (H-Tyr-d-Ala-Phe-Phe-NH ) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β - -amino acid (β hAA) scan of the TAPP sequence. To this aim, 10 novel analogues have been synthesized and evaluated for µ-opioid and δ-opioid receptor affinity as well as for stability in human plasma. The derivatives included compounds in which a ( )- or ( )-β - -Homologue replaced the amino acids in the TAPP sequence. The derivatives with ( )- or ( )-β hPhe turned out to bind µOR with affinities equal to that of the parent. β hAAs in position 1 and 3 resulted in rather large affinity decreases, but the change differed depending on the stereochemistry. β - logation in the second position gave derivatives with very poor µOR binding. According to molecular modelling, the presented α/β-peptides adopt a variety of binding poses with their common element being an ionic interaction between a protonable amine of the first residue and Asp147. A feature required for high µOR affinity seems the ability to accommodate the ring in the fourth residue in a manner similar to that found for TAPP. Contrary to what might be expected, several compounds were significantly less stable in human plasma than the parent compound.