Synthesis and biological evaluation of constrained analogues of the opioid peptide H‐Tyr‐<scp>d</scp>‐Ala‐Phe‐Gly‐NH<sub>2</sub> using the 4‐amino‐2‐benzazepin‐3‐one scaffold

Ballet, Steven; Frycia, Anne; Piron, J.; Chung, Nga N.; Schiller, Peter W.; Kossoń, Piotr; Lipkowski, Andrzej W.; Tourwé, Dirk

doi:10.1111/j.1399-3011.2005.00291.x

Cited by 35 publications

(67 citation statements)

References 19 publications

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“…Lead structure 4 was previously prepared in two main steps: a standard solid phase synthesis using the preassembled Fmoc-Aba-Gly-OH dipeptide, 31 followed by coupling of a protected tetrapeptide precursor to N Me-3’,5’-trifluoromethyl benzylamine in solution. 24 …”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

Guillemyn

Kleczkowska

Leśniak

et al. 2015

European Journal of Medicinal Chemistry

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A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3’,5’-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioral assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.

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Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

Guillemyn

Kleczkowska

Leśniak

et al. 2015

European Journal of Medicinal Chemistry

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“…18,19 To distinguish the influence of the ring constraint from that of the N -alkylation of the Gly 4 residue, the “ring opened” analogs containing an amide N-methylation were prepared, and were shown to be of equal potency. 21 Therefore, the N -methylated Lys 4 analogues of Dmt 1 -DALDA were now also investigated.…”

Section: Resultsmentioning

confidence: 99%

Variation of the Net Charge, Lipophilicity, and Side Chain Flexibility in Dmt¹-DALDA: Effect on Opioid Activity and Biodistribution

et al. 2012

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The influence of the side chain charges of the second and fourth amino acid residues in the peptidic μ opioid lead agonist Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]-DALDA) was examined. Additionally, to increase the overall lipophilicity of [Dmt1]-DALDA and to investigate the Phe3 side chain flexibility, the final amide bond was N-methylated and Phe3 was replaced by a constrained aminobenzazepine analogue. The in vitro receptor binding and activity of the peptides, as well as their in vivo transport (brain in- and efflux and tissue biodistribution) and antinociceptive properties after peripheral administration (i.p. and s.c.) in mice were determined. The structural modifications result in significant shifts of receptor binding, activity and transport properties. Strikingly, while [Dmt1]-DALDA and its N-methyl analogue, Dmt-D-Arg-Phe-NMeLys-NH2, showed a long-lasting antinociceptive effect (>7h), the peptides with D-Cit2 generate potent antinociception more rapidly (maximal effect at 1h post-injection) but also lose their analgesic activity faster, when compared to [Dmt1]-DALDA and [Dmt1,NMeLys4]-DALDA.

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“…[17,19] Both enantiomers were incorporated into the dermorphin sequence to give 5 and 6 by standard solid phase peptide synthesis by using Boc chemistry and 4-methyl-benzhydrylamine (MBHA) resin as solid support. Racemic Boc-a-MeAba-Gly was prepared starting from (R,S)-a-Meo-cyanophenylalanine, as described earlier.…”

Section: Synthesismentioning

confidence: 99%

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

et al. 2011

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Dermorphin analogues, containing a (S)- and (R)-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the α-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-α-Me-o-cyanophenylalanine precursor for (S)-α-MeAba in acceptable enantiomeric purity. However, by using a Schöllkopf chiral auxiliary, this intermediate was obtained in 88 % ee. [(S)-Aba 3-Gly 4]dermorphin retained μ-opioid affinity but displayed an increased δ-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-α-MeAba 3-Gly 4]dermorphin isomer was more potent than its S epimer. Tar-MD simulations of both non-methylated [Aba 3-Gly 4]dermorphin analogues showed a degree of folding at the C-terminal residues toward the N terminus of the peptide, without however, adopting a stabilized β-turn conformation. The α-methylated analogues, on the other hand, exhibited a type I/I' β-turn conformation over the α-MeAba 3 and Gly 4 residues, which was stabilized by a hydrogen bond involving Tyr 5-HN and D-Ala 2-CO.

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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

Cited by 35 publications

References 19 publications

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

Variation of the Net Charge, Lipophilicity, and Side Chain Flexibility in Dmt¹-DALDA: Effect on Opioid Activity and Biodistribution

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

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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

Cited by 35 publications

References 19 publications

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

Variation of the Net Charge, Lipophilicity, and Side Chain Flexibility in Dmt1-DALDA: Effect on Opioid Activity and Biodistribution

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

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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

Variation of the Net Charge, Lipophilicity, and Side Chain Flexibility in Dmt¹-DALDA: Effect on Opioid Activity and Biodistribution