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

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.