179188-06-8Relevant articles and documents
Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin
Joshi, Anand A.,Murray, Thomas F.,Aldrich, Jane V.
, p. 8783 - 8795 (2015)
The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr1-cyclo(d-Asp5,Dap8)]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR)-selective antagonist in vitro, is active in vivo, and antagonizes KOR in the CNS
Multiply substituted DTPA derivatives and their metal complexes, and their metal complexes, pharmaceutical agents that contain these complexes, their use in diagnosis and therapy, as well as process for the production of pharmaceutical agents
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, (2008/06/13)
The invention relates to new, multiply substituted diethylenetriaminepentaacetic acid derivatives, their complexes and complex salts, that contain an element of atomic numbers 20-32, 39-51 or 57-83, pharmaceutical agents that contain these compounds, their use as contrast media and antidotes, and process for the production of pharmaceutical agents.
DTPA derivatives substituted in a novel way, their metal complexes, and their use in diagnosis and therapy
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, (2008/06/13)
The invention relates to new diethylenetriaminepentaacetic acid derivatives, their complexes and complex salts, that contain an element of atomic numbers 20-32, 39-51 or 57-83, pharmaceutical agents that contain these compounds and their use as contrast m
Synthesis and opioid activity of [D-Pro10]Dynorphin A-(1-11) analogues with N-terminal alkyl substitution
Choi, Heekyung,Murray, Thomas F.,DeLander, Gary E.,Schmidt, William K.,Aldrich, Jane V.
, p. 2733 - 2739 (2007/10/03)
Several N-terminal di- and monoalkylated derivatives of [D- Pro10]dynorphin A-(1-11) were synthesized in order to explore the structure-activity relationships for antagonist vs agonist activity at κ- opioid receptors. N,N-Dialkylated and N-monoalkylated (alkyl = allyl, benzyl, and cyclopropylmethyl (CPM)) tyrosine derivatives were prepared from tyrosine tert-butyl ester and the corresponding alkyl halides. [D-Pro10]Dyn A-(2- 11) was prepared by solid phase synthesis using Fmoc-protected amino acids, and the tyrosine derivatives were coupled to the peptide with BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate). Both the degree of substitution and the identity of the alkyl group affected κ-receptor affinity, selectivity, and efficacy. All of the N-monoalkylated derivatives exhibited much higher affinity (K(i) 200) compared to the N,N-dialkyl [D-Pro10]Dyn A-(1- 11) analogues, although one disubstituted analogue, N,N-diCPM[D-Pro10]Dyn A-(1-11), retained high affinity (K(i) = 0.19 nM) for κ receptors. Thus the introduction of the second alkyl group at the N-terminus lowered κ-receptor affinity and selectivity. The N-allyl and N-CPM analogues were moderately potent agonists in the guinea pig ileum (GPI) assay, while the N-benzyl derivative was a weak agonist in this assay. In vivo in the phenylqninone abdominal stretching assay the N-CPM analogue exhibited potent antinociceptive activity (ED50 = 1.1 μg/mouse), while N-allyl[D- Pro10]Dyn A-(l-11) exhibited weak antinociceptive activity (ED50 = 27 μg/mouse). For the N,N-dialkyl derivatives the identity of the N-terminal alkyl group affected the efficacy observed in the smooth muscle assays. The N,N-diCPM analogue exhibited negligible agonist activity, and N,N-diallyl[D- Pro10]Dyn A-(l-11) showed weak antagonist activity against Dyn A-(1- 13)NH2 in the GPI. In contrast, the N,N-dibenzyl compound showed appreciable opioid agonist activity in this assay. In vivo the N,N-diallyl analogue exhibited weak antinociceptive activity (ED50 = 26 μg/mouse in the phenylquinone abdominal stretching assay). The N-monoalkylated peptides are among the most κ-selective opioid peptides reported to date, showing comparable or greater selectivity and higher affinity than the κ-selective nonpeptide agonists U-50,488 and U-69,593. The N,N-diCPM and N,N-diallyl peptides are lead compounds in the development of peptide-based κ-receptor antagonists.
