β2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-05, Vol.25 (10), p.2461
• Main Authors: Tymecka, Dagmara, Lipiński, Piotr F. J., Kosson, Piotr, Misicka, Aleksandra
• Format: Article
• Language: English
• Subjects: Affinity; Amino acid sequence; Amino acids; Binding; Blood plasma; Chromatography; Homology; Ionic interactions; Molecular modelling; Narcotics; opioid peptides; Opioid receptors; Peptides; Phenols; racemic synthesis of β2-amino acids; Residues; Stereochemistry; TAPP; β2-amino acids; β2-Homo-amino acids; µ-opioid receptor
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25102461

TAPP (H-Tyr-d-Ala-Phe-Phe-NH2) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β2-Homo-amino acid (β2hAA) 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 (R)- or (S)-β2-Homo-Homologue replaced the amino acids in the TAPP sequence. The derivatives with (R)- or (S)-β2hPhe4 turned out to bind µOR with affinities equal to that of the parent. β2hAAs in position 1 and 3 resulted in rather large affinity decreases, but the change differed depending on the stereochemistry. β2-Homologation 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.