Synthesis of 4-amino-3-oxo-tetrahydroazepino[3,4-b]indoles: new conformationally constrained Trp analogs

Pulka, Karolina; Feytens, Debby; Eynde, Isabelle Van den; Wachter, Rien De; Kossoń, Piotr; Misicka, Aleksandra; Lipkowski, Andrzej W.; Chung, Nga N.; Schiller, Peter W.; Tourwé, Dirk

doi:10.1016/j.tet.2006.11.069

Cited by 26 publications

(38 citation statements)

References 40 publications

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“…The 4-amino-indolo[2,3-c]azepin-3-one scaffold (Aia) in 3 can be regarded as a constrained tryptophan residue that limits both χ 1 and χ 2 dihedral angles in the same way as the Aba scaffold does for a phenylalanine residue 17, 41. Structurally, the introduction of Aia into the opioid pharmacophore can, for example, mimic Trp3 as was shown in the endogenous endomorphin-1 (EM-1: H-Tyr 1 -Pro 2 -Trp 3 -Phe 4 -NH 2 ).…”

mentioning

confidence: 99%

Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold

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Feytens

Wachter

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent μ-selective agonists (Structures 5 and 12) as well as potent and selective δ-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,Ndimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small peptidomimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure-activity data.Conformationally constrained amino acids have found widespread application in search of novel peptidic opioid ligands with minored side-effects. 1-8 Such residues, inducing enhanced receptor selectivity and affinity, can be subdivided in sterically (e.g., β-methylphenylalanine, β-methyltryptophan, β-methyl-2′,6′-dimethyltyrosine) and covalently constrained derivatives [e.g., 2-aminotetralin-2-carboxylic acid (Atc), 2-aminoindane-2-carboxylic acid (Aic), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic)]. 9 The Dmt-Tic scaffold 1, in particular, has been recognized as a firmly established template for opioid ligand design. 3,4 Subtle changes in this scaffold have induced remarkable alterations in opioid receptor selectivity and/or activity, such as enhanced agonism, antagonism, or the acquisition of mixed activities at the opioid subtype receptors (i.e., μ, δ and κ receptors). Replacement of tyrosine by Dmt (2′,6′-

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confidence: 99%

Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold

Ballet

Feytens

Wachter

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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“…Aromatic amino acids (Phe, Tyr, Trp, and His) are often a key element in bioactive peptides [5]. The procedure allows the introduction of a variety of substituents (halogens) at the phenylalanine derivatives.…”

Section: Resultsmentioning

confidence: 99%

Conformationally Constrained Ac-His-D-Nal(2’)-Nle-Trp-NH2 Analogues Leads to Selective Melanotropins

Haghighi¹,

Cai²,

Zhou³

et al. 2015

Peptides 2015, Proceedings of the 24th American Peptide Symposium

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“…Boc-2′-formyl-D-tryptophan 4 was prepared by SeO 2 oxidation of 2-(tert-butoxycarbonyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid (Boc-D-Tcc) as described previously. 21 Reductive amination with ε-Cbzprotected lysine methyl ester and NaBH 3 CN, immediately followed by cyclization using EDC/pyridine, yielded 6. In contrast to our previous findings, 16 the cyclization was complete after overnight stirring.…”

Section: Resultsmentioning

confidence: 99%

“…51 Boc-2′-formyl tryptophan 4 was prepared as described previously. 21 Synthesis and characterization of compound 8 were published previously. 16 Thin layer chromatography (TLC) was performed on plastic sheet precoated with silica gel 60F 254 (Merck, Darmstadt, Germany) using specified solvent systems.…”

Section: Methodsmentioning

confidence: 99%

Highly Potent 4-Amino-indolo[2,3-c]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

et al. 2008

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The synthesis, biological evaluation, and conformational analysis of 4-amino-indolo[2,3-c]azepin-3-one (Aia)-containing SRIF mimetics are reported. Different subtype selectivities are observed depending on the N- and C-terminal substituents of the D-Aia-Lys dipeptide mimetic. An sst(5)-selective analogue with subnanomolar binding affinity was obtained that is the most potent agonist reported to date. A nonselective mimetic with high potency was also identified. This study allows a better definition of the bioactive conformation of the essential D-Trp side chain in the somatostatin pharmacophore.

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Synthesis of 4-amino-3-oxo-tetrahydroazepino[3,4-b]indoles: new conformationally constrained Trp analogs

Cited by 26 publications

References 40 publications

Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold

Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold

Conformationally Constrained Ac-His-D-Nal(2’)-Nle-Trp-NH2 Analogues Leads to Selective Melanotropins

Highly Potent 4-Amino-indolo[2,3-c]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

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