Conformational restriction of Tyr1 and Phe3 side chains in opioid peptides: Evidence that the trans conformation at χ1 is required for δ-selectivity

Tourwé, Dirk; Conrath, P.; Frycia, Anne; Verschueren, Karine; Jaspers, H.; Verheyden, Patricia; Betsbrugge, J. Van; Binst, G. Van

doi:10.1007/978-94-011-1468-4_322

Cited by 4 publications

(4 citation statements)

References 5 publications

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“…This modification alone has shifted the selectivity profile for this DRM analog from μ- to δ-selectivity. This trend was observed recently by the same group with other conformationally restricted opioid peptides . On the other hand, [Tic 3 ]-DRM, where the Phe side chain was fixed into the g + rotamer (Tic is a tetrahydroisoquinoline-3-carboxylic acid), was inactive on both receptor types .…”

Section: Introductionsupporting

confidence: 76%

Design and Comprehensive Conformational Studies of Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-l-3-Mpt⁵) and Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-d-3-Mpt⁵): Novel Conformationally Constrained Opioid Peptides

Nikiforovich¹,

Kövér²,

Kolodziej³

et al. 1996

J. Am. Chem. Soc.

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Two compounds, Tyr 1 -cyclo(D-Pen 2 -Gly 3 -Phe 4 -L-3-Mpt 5 ) (DPMPT; 3-Mpt is trans-3-mercaptoproline) and Tyr 1 -cyclo(D-Pen 2 -Gly 3 -Phe 4 -D-3-Mpt 5 ) (DPDMPT), were designed employing energy calculations. Geometrical comparison showed that some low-energy 3D structures of DPMPT and DPDMPT are compatible with the model for the δ-receptor-bound conformation of the well-known δ-selective DPDPE peptide Tyr 1 -cyclo(D-Pen 2 -Gly 3 -Phe 4 -D-Pen 5 , which was proposed by us earlier. DPMPT and DPDMPT were tested for their binding to δ-, µand κ-opioid receptors. The corresponding K i values were 3.5, 68, and >5000 nM for DPMPT, and 103.7, >5000, and >5000 nM for DPDMPT, respectively. Independent studies by homo-and heteronuclear NMR spectroscopy and energy calculations showed that DPMPT exists in DMSO solution in conformational equilibrium among several backbone conformations with the same type of 3D structure for the cyclic moiety, but with somewhat different conformers of the acyclic part of the molecule and two types of rotamers for the D-Pen side chain, namely, t and g -. For DPDMPT, energy calculations combined with the NMR data suggest that any one out of four low-energy conformers belonging to the same type of the backbone of the cyclic moiety may be a possible candidate for the DPDMPT conformer in DMSO. The DPDMPT structure revealed by X-ray crystallography showed remarkable similarity to DPDMPT solution conformations. The determined solution conformations of both compounds were compared to their suggested δ-receptor-bound conformers. Results of comparison showed that all four of the possible solution conformations of DPDMPT are nonsimilar to the DPDMPT δ-receptor-bound conformation, whereas two of the possible solution conformations of DPMPT are compatible with the suggested δ-receptor-bound conformation of DPMPT. This finding can explain the difference in binding of DPMPT and DPDMPT to δ-opioid receptors by a suggestion that the δ-receptor-bound conformation of DPMPT already preexists in solution, whereas solution conformations of DPDMPT should be more significantly distorted to match the δ-receptor-bound conformation of DPDMPT.

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Section: Introductionsupporting

confidence: 76%

Design and Comprehensive Conformational Studies of Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-l-3-Mpt⁵) and Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-d-3-Mpt⁵): Novel Conformationally Constrained Opioid Peptides

Nikiforovich¹,

Kövér²,

Kolodziej³

et al. 1996

J. Am. Chem. Soc.

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“…However, the high δ affinity of the Hba 1 -deltorphin II analogue, 38 which cannot adopt a gauche(-) conformation, strongly suggests that the Hat 1 -deltorphin analogues switch from their preferred conformation in solution to a trans conformation during receptor interaction.…”

Section: Discussionmentioning

confidence: 99%

Deltorphin II Analogues with 6-Hydroxy-2-aminotetralin-2-carboxylic Acid in Position 1

et al. 2000

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Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorphin analogues with altered hydrophobic and stereoelectronic properties. Deltorphin II analogues were synthesized with the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 6-hydroxy-2-aminotetralin-2-carboxylic acid (Hat) instead of Tyr(1) in the message domain. In the radioreceptor-binding studies, in which type-specific tritiated opioid ligands were used, (R)- and (S)-Hat-deltorphins exhibited similar K(i) values, revealing high delta selectivity. The peptides displayed agonist properties in the in vitro bioassay, with IC(50) values in the subnanomolar range in the mouse vas deferens assay and in the micromolar or higher range in the guinea pig ileum assay, again demonstrating a high selectivity toward delta receptors. The agonist property of the new ligands was confirmed by means of [(35)S]GTPgammaS-binding experiments in membranes of the rat frontal cortex.

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“…Restrictions in the conformational flexibility of dermorphin have resulted in remarkable selectivity and affinity shifts (5–8). The introduction of the dipeptidic moiety 4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one (Aba)‐Gly in positions 3 and 4, led to a substantial increase of the δ ‐affinity of the dermorphin analogue [Aba 3 ‐Gly 4 ]dermorphin‐NH 2 (5).…”

Section: Introductionmentioning

confidence: 99%

“…A similar fixation of the Tyr 1 side chain in [8‐hydroxy‐4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one (Hba) 1 ‐ d ‐Ala 2 ]dermorphin‐NH 2 did not influence the μ ‐binding and increased δ ‐affinity by a factor of 6. Molecular modelling and NMR data indicated for both Hba 1 and Aba 3 the trans ‐conformation at χ 1 , when integrated into peptides [Hba 1 ‐ d ‐Ala 2 ]dermorphin‐NH 2 and [Aba 3 ‐Gly 4 ]dermorphin‐NH 2 (7).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of constrained analogues of the opioid peptide H‐Tyr‐d‐Ala‐Phe‐Gly‐NH₂ using the 4‐amino‐2‐benzazepin‐3‐one scaffold

Ballet

Frycia

Piron

et al. 2005

The Journal of Peptide Research

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The synthesis of conformationally restricted dipeptidic moieties 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba)-Gly ([(4S)-amino-3-oxo-1,2,4,5-tetrahydro-1H-2-benzazepin-2-yl]-acetic acid) and 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba)-D-Ala ([(4S)-amino-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-benzo[c]azepin-2-yl]-propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N-acyliminium precursor. Introducing these Aba scaffolds into the N-terminal tetrapeptide of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2)-induced remarkable shifts in affinity and selectivity towards the opioid mu- and delta-receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N-terminal tetrapeptide H-Tyr-D-Ala-Phe-Gly-NH2, which is the minimal subunit of dermorphin needed for dermorphin-like opiate activity.

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Conformational restriction of Tyr1 and Phe3 side chains in opioid peptides: Evidence that the trans conformation at χ1 is required for δ-selectivity

Cited by 4 publications

References 5 publications

Design and Comprehensive Conformational Studies of Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-l-3-Mpt⁵) and Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-d-3-Mpt⁵): Novel Conformationally Constrained Opioid Peptides

Design and Comprehensive Conformational Studies of Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-l-3-Mpt⁵) and Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-d-3-Mpt⁵): Novel Conformationally Constrained Opioid Peptides

Deltorphin II Analogues with 6-Hydroxy-2-aminotetralin-2-carboxylic Acid in Position 1

Synthesis and biological evaluation of constrained analogues of the opioid peptide H‐Tyr‐d‐Ala‐Phe‐Gly‐NH₂ using the 4‐amino‐2‐benzazepin‐3‐one scaffold

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Conformational restriction of Tyr1 and Phe3 side chains in opioid peptides: Evidence that the trans conformation at χ1 is required for δ-selectivity

Cited by 4 publications

References 5 publications

Design and Comprehensive Conformational Studies of Tyr1-cyclo(d-Pen2-Gly3-Phe4-l-3-Mpt5) and Tyr1-cyclo(d-Pen2-Gly3-Phe4-d-3-Mpt5): Novel Conformationally Constrained Opioid Peptides

Design and Comprehensive Conformational Studies of Tyr1-cyclo(d-Pen2-Gly3-Phe4-l-3-Mpt5) and Tyr1-cyclo(d-Pen2-Gly3-Phe4-d-3-Mpt5): Novel Conformationally Constrained Opioid Peptides

Deltorphin II Analogues with 6-Hydroxy-2-aminotetralin-2-carboxylic Acid in Position 1

Synthesis and biological evaluation of constrained analogues of the opioid peptide H‐Tyr‐d‐Ala‐Phe‐Gly‐NH2 using the 4‐amino‐2‐benzazepin‐3‐one scaffold

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Design and Comprehensive Conformational Studies of Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-l-3-Mpt⁵) and Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-d-3-Mpt⁵): Novel Conformationally Constrained Opioid Peptides

Design and Comprehensive Conformational Studies of Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-l-3-Mpt⁵) and Tyr¹-cyclo(d-Pen²-Gly³-Phe⁴-d-3-Mpt⁵): Novel Conformationally Constrained Opioid Peptides

Synthesis and biological evaluation of constrained analogues of the opioid peptide H‐Tyr‐d‐Ala‐Phe‐Gly‐NH₂ using the 4‐amino‐2‐benzazepin‐3‐one scaffold