Structural studies with weak oxytocin antagonists

Assimomytis, Nikos; Magafa, Vassiliki; Theodoropoulos, Dimitrios; Cordopatis, Paul; Slaninová, Jiřina

doi:10.1007/bf00128110

Cited by 4 publications

(1 citation statement)

References 15 publications

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“…In addition to modifying the pharmacophore of small peptides, Aib‐substitution could also enhance resistance to proteases. Based upon our studies with Aib‐substituted oxytocins (Assisomytis et al ., 1996), we chose to introduce Aib at positions 4, 7 and 9 of vasopressin analogues as these positions have been successfully modified in the design of many selective neurohypophysial hormone analogues (for reviews see Lebl et al ., 1987; Manning et al ., 1987a). Whilst inter‐specific differences in the pharmacology of vasopressin analogues are possible, our bioassays revealed that both [Aib 4 ]AVP and [Aib 7 ]AVP are V 2 ‐selective agonists in the rat.…”

Section: Discussionmentioning

confidence: 99%

Novel strategies for the design of receptor‐selective vasopressin analogues: Aib‐substitution and retro‐inverso transformation

Howl

Procházka

Wheatley

et al. 1999

British J Pharmacology

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1 We determined the pharmacological pro®le of novel backbone-modi®ed peptides designed as protease-resistant, selective analogues of AVP. Binding anities of peptides were determined at both V 1A and V 2 subtypes of vasopressin receptor (VPR). Biological potencies of selected peptides were tested in pressor and antidiuretic bioassays. 9 ]AVP bound selectively and with high anity (K d 0.51 and 4.1 nM respectively) to the V 1A VPR. Bioassays con®rmed that these peptides were potent antivasopressor agents (pA 2 8.10 and 8.36 respectively). 4 A total retro-inverso strategy was used to prepare protease-resistant mimetics of both AVP and linear V 1A -selective antagonists. Cyclic retro-inverso mimetics of AVP did not bind either V 1A or V 2 VPRs. In contrast, rationally designed retro-inverso mimetics of linear V 1A -selective antagonists selectively bound the V 1A VPR. 5 Our ®ndings indicate novel methods to improve the pharmacodynamic and pharmacokinetic parameters of neurohypophysial hormone analogues which could be equally applicable to other peptide-receptor systems.

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Section: Discussionmentioning

confidence: 99%

Novel strategies for the design of receptor‐selective vasopressin analogues: Aib‐substitution and retro‐inverso transformation

Howl

Procházka

Wheatley

et al. 1999

British J Pharmacology

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Synthesis and biological activity of oxytocin analogues containing unnatural amino acids in position 9: structure activity study

et al. 2009

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We report the solid phase synthesis and some pharmacological properties of 24 oxytocin (OT) analogues. Basic modifications at position 9 (introduction of L- or D-beta-(2-thienyl)-alanine [L- or D-Thi], or L- or D-3-Pyridylalanine [L- or D-3-Pal]) were combined with D-tyrosine(OEthyl) [D-Tyr(Et)] or D-1-naphthylalanine [D-1-Nal] in position 2 and beta-mercaptopropionic acid (Mpa) in position 1 modifications in altogether 14 analogues. Additionally, 8 analogues having alpha-aminoisobutyric acid [Aib] or D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (D-Tic) or diethylglycine (Deg) in position 9 and D-Tyr(Et) or D-1-Nal or D-Tic in position 2 and Mpa or Pen (beta beta-dimethylcysteine) in position 1 were prepared. Two of these analogues have one more modification in position 6, i.e. Pen. Furthermore, two analogues having Mpa in position 1 and D-Tyr(Et) or D-1-Nal in position 2 were prepared for comparison purposes. The analogues were tested for rat uterotonic activity in vitro, in the rat pressor assay and for binding affinity to human OT receptor. The analogue having the highest anti-oxytocic activity was [Mpa(1), D-Tyr(Et)(2), Deg(9)]OT (pA(2) = 8.68 +/- 0.26); this analogue was also selective.

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Synthesis and biological activity of oxytocin analogues containing conformationally-restricted residues in position 7

Fragiadaki

Magafa

Borovičková

et al. 2007

European Journal of Medicinal Chemistry

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Structural studies with weak oxytocin antagonists

Cited by 4 publications

References 15 publications

Novel strategies for the design of receptor‐selective vasopressin analogues: Aib‐substitution and retro‐inverso transformation

Novel strategies for the design of receptor‐selective vasopressin analogues: Aib‐substitution and retro‐inverso transformation

Synthesis and biological activity of oxytocin analogues containing unnatural amino acids in position 9: structure activity study

Synthesis and biological activity of oxytocin analogues containing conformationally-restricted residues in position 7

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