Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds

Ballet, Steven; Marczak, Ewa D.; Feytens, Debby; Salvadori, Severo; Sasaki, Yoshiyuki; Abell, Andrew D.; Lazarus, Lawrence H.; Balboni, Gianfranco; Tourwé, Dirk

doi:10.1016/j.bmcl.2010.01.055

Cited by 7 publications

(4 citation statements)

References 40 publications

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“…Earlier results have demonstrated that the use of the Aba scaffold in opioid peptides results in very potent agonists with high receptor affinity. ,− Several examples were reported in which Aba serves as the third residue in synthetic peptidic opioid ligands (e.g., Tyr 1 - d -Ala 2 -Aba 3 -Gly 4 -NH 2 and Tyr 1 - d -Ala 2 -Aba 3 -Gly 4 -Tyr 5 -Pro 6 -Ser 7 -NH 2 ) . This conformational constraint yields a substantial enhancement in DOR affinity, while maintaining MOR binding and functional activity.…”

Section: Resultsmentioning

confidence: 99%

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Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist

et al. 2011

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A screening of conformationally constrained aromatic amino acids as base cores for the preparation of new NK1 receptor antagonists resulted in the discovery of three new NK1 receptor antagonists, 19 [Ac-Aba-Gly-NH-3′,5′-(CF3)2-Bn], 20 [Ac-Aba-Gly-NMe-3′,5′-(CF3)2-Bn] and 23 [Ac-Tic-NMe-3′,5′-(CF3)2-Bn], which were able to counteract the agonist effect of substance P, the endogenous ligand of NK1R. The most active NK1 antagonist of the series, 20 [Ac-Aba-Gly-NMe-3′,5′-(CF3)2-Bn], was then used in the design of a novel, potent chimeric opioid agonist-NK1 receptor antagonist, 35 [Dmt-D-Arg-Aba-Gly-NMe-3′,5′-(CF3)2-Bn], which combines the N-terminus of the established Dmt1-DALDA agonist opioid pharmacophore (H-Dmt-D-Arg-Phe-Lys-NH2) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, i.e. Dmt-D-Arg-Aba-Gly-NH2 36, also proved to be an extremely potent and balanced μ- and δ opioid receptor agonist with subnanomolar binding and in vitro functional activity.

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Section: Resultsmentioning

confidence: 99%

“…30,43–45 Several examples were reported in which Aba serves as the third residue in synthetic peptidic opioid ligands (e.g. Tyr 1 -D-Ala 2 -Aba 3 -Gly 4 -NH 2 , 39 Tyr 1 -D-Ala 2 -Aba 3 -Gly 4 -Tyr 5 -Pro 6 -Ser 7 -NH 2 .…”

Section: Biological Evaluation and Structure-activity Relationshipsmentioning

confidence: 99%

Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist

et al. 2011

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“…Azepinone scaffold has been utilized for the formation of constrained dipeptidic moieties such as Aba, 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba), and 4-mino-1,2,4,5-tetrahydro-indolo [2,3-c]azepin-3-one (Aia). Replacement of Tic-Gly in Dmt-Tic-Gly analogs with dipeptidic moieties, Aba-Gly and D Aia-Gly, shifted affinity and selectivity to afford a potent MOR agonist and DOR antagonist, respectively [ 283 , 284 , 285 , 286 ]. The same replacement effect was observed in DER tetrapeptide when Phe 3 -Gly 4 was substituted by Aba-Gly [ 287 ].…”

Section: Peptidomimetics For Opioid Receptorsmentioning

confidence: 99%

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Lee

2022

Biomolecules

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Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures.

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“…Both compounds belong to the subclass of “merged” DMLs, in which the two pharmacophores, interacting with two different targets, overlap (Figure ). The opioid agonist part is derived from the μ opioid receptor agonist Dmt- d -Arg-Phe-Lys-NH 2 ([Dmt] 1 -DALDA 3 ) and contains the 4-amino-2-benzazepin-3-one (Aba) scaffold, a conformationally constrained amino acid used in the design of very potent opioid agonists. − The Aba scaffold is also part of the NK1 pharmacophore and enabled the design of very compact chimeric compounds.…”

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Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

Betti

Starnowska

Mika

et al. 2015

ACS Med. Chem. Lett.

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Herein, the synthesis and biological evaluation of dual opioid agonists−neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ-and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.

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Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds

Cited by 7 publications

References 40 publications

Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist

Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

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