Synthesis and biological evaluations of novel endomorphin analogues containing α-hydroxy-β-phenylalanine (AHPBA) displaying mixed μ/δ opioid receptor agonist and δ opioid receptor antagonist activities

Hu, Miao; Giulianotti, Marc A.; McLaughlin, Jay P.; Shao, Jiaan; Debevec, Ginamarie; Maida, Laura; Geer, Phaedra; Cazares, Margaret E.; Misler, Jaime A.; Li, Ling; Dooley, Colette T.; Ganno, Michelle L.; Eans, Shainnel O.; Mizrachi, Elisa; Santos, Radleigh; Yongye, Austin B.; Houghten, Richard A.; Yu, Yongping

doi:10.1016/j.ejmech.2014.12.049

Cited by 17 publications

(19 citation statements)

References 69 publications

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“…The antinociceptive activity of 14 was equal to that of morphine in the mouse warm-water (55°C) tail-withdrawal test. In conclusion, the replacement of Tyr 1 -Pro 2 by Dmt 1 -Tic 2 and the introduction of α-hydroxy-β-amino acid led to a dramatic increase in enzymatic stability of the EM analogues [15].…”

Section: Em Analogues Containing Modified Prolinementioning

confidence: 89%

“…NorCal Open Access Publications Journal of Biochemistry and Chemical Sciences Volume 1; Issue 1 De Marco R [12,13] [14] [14] [15] [15] [16] H-Tyr-Sar-Phe-PheNH 2 [17,18] [ 17,18] [ [19][20][21][22] [c[Tyr-D-Pro-D-Trp-Phe-Gly [19,21,22] [c[Tyr-Gly-D-Trp-Phe-Gly [23] Ac-D-Trp-Phe-GlyNH 2 [24] Ac-5-NO 2 -D-Trp-Phe-GlyNH 2 [24] Ac-7-Br-2-Me-D-Trp-Phe-GlyNH 2 [25] H-Tyr-Pro-Phe-D-Val-NH 2 [26] [27] H-Tyr-Pro-Phe-PheNHNH 2 [27] H-Tyr-Pro-Trp-PheNHNH 2 [28] 27 [28] 28 [29] 29 [30] 30 [30] H-Tyr-Pro-Trp-(2R,3R)βMe-PheNH 2 31 [30] H-Tyr-Pro-Trp-(2S,3S)βMe-PheNH 2 32 [31] 33 [32] [C8Laa-Dmt]-Pro-Trp-PheNH 2 34 [33] 35 [34][35][36] 36 [37] Tyr-c[D-Lys-Phe-Phe-Asp]NH 2 37 [38] (Tyr-c[D-Lys-Phe-Phe-Asp]NH 2 ) 2 38 J Biochem Chem Sci 2017: 14-23.…”

Section: Norcal Open Access Publicationmentioning

confidence: 99%

“…This EM1 mimetic is the first analogue of EM1 showing antinociceptive activity after systemic administration. Yu et al, in 2015 combined the introduction of Tic, i.e., 1,2,3,4-tetrahydroisoquinoline carboxylic acid, in place of Pro 2 , and of α-hydroxy-β-amino acids instead of Tryptophan (Trp) and Phenylalanine (Phe) at positions 3 and 4, respectively [15]. The resulting analogues H-Dmt-TicTrp-(2S,3S)AHPBA-NH 2 (Table1, 13) and H-Dmt-Tic-(2R,3S)AHPBA-Phe-NH 2 (Table 1, 14), showed a great increase in enzymatic stability (t1/2>2 h).…”

Section: Em Analogues Containing Modified Prolinementioning

confidence: 99%

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

2017

JCAR

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The neurophysiological distribution of the Endomorphins (EMs), i.e., Endomorphin-1 (EM1) and Endomorphin-2 (EM2), reflects their potential role in many major biological processes. These include perception of pain, responses related to stress, and complex functions such as reward, arousal, and vigilance, as well as autonomic, cognitive, neuroendocrine, and limbic homeostasis. In particular, EM1 and EM2 have demonstrated potent antinociception without some of the undesired side effects of opiate drugs. Unfortunately, their clinical applications as painkillers remain unrealistic due to their poor metabolic stability, inability to cross the Blood-Brain Barrier (BBB), and efficient efflux. In this review is reported a brief collection of recently published modified endomorphins, for which the potentiality as painkiller was clearly demonstrated in vitro and in vivo. Selected structures of bioactive EM analogues highlighting the modified residues, with references, are reported in the table of the review.

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Section: Em Analogues Containing Modified Prolinementioning

confidence: 89%

Section: Norcal Open Access Publicationmentioning

confidence: 99%

Section: Em Analogues Containing Modified Prolinementioning

confidence: 99%

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

2017

JCAR

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“…It is also polysubstituted β-AAs that were used in the opioid field. For example, several recent papers dealt with endomorphin-1/-2 analogues containing one or more β 2,3 -AAs [21][22][23][24][25]. Peptides are endogenous ligands for all types of opioid receptors (µ, δ, κ, and nociceptin) [4].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…Dmt-Tic was embedded into the sequence of various MOR-selective ligands, producing compounds with interesting biological activities. EM-2 analog, Dmt-Tic-(2 R ,3 S )AHPBA-Phe-NH 2 , incorporating α-hydroxy-β-phenylalanine (AHPBA) showed an MOR agonist/DOR partial agonist profile and in the in vivo studies in mice produced comparable with morphine antinociception but did not demonstrate acute antinociceptive tolerance [ 22 ]. The distance between the Dmt-Tic pharmacophore and the third aromatic residue in the peptide sequence was found to be responsible for converting potent Dmt-Tic-based DOR-antagonists into non-selective ligands with an MOR agonist/DOR antagonist profile.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Functional Analysis of Cyclic Opioid Peptides with Dmt-Tic Pharmacophore

Sarkar

Adamska‐Bartłomiejczyk

Piekielna-Ciesielska

et al. 2020

Molecules

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The opioid receptors are members of the G-protein-coupled receptor (GPCR) family and are known to modulate a variety of biological functions, including pain perception. Despite considerable advances, the mechanisms by which opioid agonists and antagonists interact with their receptors and exert their effect are still not completely understood. In this report, six new hybrids of the Dmt-Tic pharmacophore and cyclic peptides, which were shown before to have a high affinity for the µ-opioid receptor (MOR) were synthesized and characterized pharmacologically in calcium mobilization functional assays. All obtained ligands turned out to be selective antagonists of the δ-opioid receptor (DOR) and did not activate or block the MOR. The three-dimensional structural determinants responsible for the DOR antagonist properties of these analogs were further investigated by docking studies. The results indicate that these compounds attach to the DOR in a slightly different orientation with respect to the Dmt-Tic pharmacophore than Dmt-TicΨ[CH2-NH]Phe-Phe-NH2 (DIPP-NH2[Ψ]), a prototypical DOR antagonist peptide. Key pharmacophoric contacts between the DOR and the ligands were maintained through an analogous spatial arrangement of pharmacophores, which could provide an explanation for the predicted high-affinity binding and the experimentally observed functional properties of the novel synthetic ligands.

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Synthesis and biological evaluations of novel endomorphin analogues containing α-hydroxy-β-phenylalanine (AHPBA) displaying mixed μ/δ opioid receptor agonist and δ opioid receptor antagonist activities

Cited by 17 publications

References 69 publications

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

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

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

Design, Synthesis and Functional Analysis of Cyclic Opioid Peptides with Dmt-Tic Pharmacophore

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