The Effect of Pro² Modifications on the Structural and Pharmacological Properties of Endomorphin-2

Abstract

Endomorphins (EM-1 and EM-2) are selective, high affinity agonists of the μ-opioid (MOP) receptor, an important target in pain regulation. Their clinical use is impeded by their poor metabolic stability and limited entry to the central nervous system. In this study, the Pro(2) residue of EM-2 was modified systematically through substitution by hydroxyproline (Hyp), (S)-β-homoproline (βPro), 2-aminocyclopentene-1-carboxylic acid (ΔAcpc), or 2-aminocyclohexene-1-carboxylic acid (ΔAchc) to obtain stable MOP active compounds. Both Hyp(2) and βPro(2) substitution decreased receptor affinity. Analogues incorporating alicyclic β-amino acids exhibited diverse receptor binding properties, depending on the configuration of the substituent side-chain. (1S,2R)ΔAcpc(2)-EM-2 was shown to have MOP affinity and selectivity comparable to those of EM-2 and proved to act as agonist while being resistant to proteolysis. NMR and molecular dynamics (MD) studies revealed that bent backbone structures are predominant in the most potent analogues, while their presence is less pronounced in ligands of lower receptor affinity.

Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives

“…In this regard, backbone conformations and side-chain arrangement of various EM analogues were investigated. [17][18][19][20][21][22] As linear peptides often exist in conformational equilibrium, cyclic peptides which adopt better defined conformations were used in many structural studies aimed at understanding the specific requirements of each opioid receptor type. [23][24][25][26] Over the last several years, we have focused our research on the synthesis of cyclic analogues based on the sequence of EM-2, with incorporated bifunctional amino acids that facilitated ring closure.…”

A Brief Survey on Recent Endomorphin-1 and Endomorphin-2 Analogues

“…At present, their clinical use as painkillers is hampered, due to their low metabolic stability [45,46], inability to cross the Blood-Brain Barrier (BBB), and efficient efflux [47,48]. As a consequence, in the recent years, many structural modifications have been introduced into EMs to improve their pharmacological properties: incorporation of unnatural amino acids [49][50][51] introduction of structural constraints [52] nitrogen quaternization [45] alteration of lipophilicity [33,53] replacement of the natural L-amino acids by their D-enantiomers [51] N-alkylation [54,55] introduction of α-substituted α-amino acids [51] β-substituted α-amino acids [51] proline analogues [56][57][58] γ-and β-amino acids [59][60][61][62][63] substituted β-amino acids [64]. These issues have been extensively reviewed elsewhere [3,41,50,51,64].…”

Solid-Phase Azopeptide Diels–Alder Chemistry for Aza-pipecolyl Residue Synthesis To Study Peptide Conformation

“…Morphiceptin (H-Tyr-Pro-Phe-Pro-NH 2 ), endomorphin-1 (H-Tyr-Pro-Trp-Phe-NH 2 ), and endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH 2 ) were selected due to their agonist activity and high selectivity for the μ-opioid (MOP) receptors . Dynamic equilibria about the Tyr-Pro prolyl amide and a cis conformer have been supported for the activity of these opioid peptides using a series of Pro surrogates, combined with ring-substituted Tyr and Phe residues . Moreover, an active Dmt-Tic amide cis -isomer was concluded on the basis of the crystal structure of the bifunctional MOP agonist/δ-opioid (DOP) receptor antagonist Dmt-Tic-Phe-Phe-NH 2 (Dmt = 2′,6′-dimethyltyrosine, Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylate) complexed with the human DOP receptor …”