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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010New Analogues of Arginine Vasopressin and Its SelectedAgonists Modified at Position 2 with (S)-2-(1-Adamantyl)glycineBernard Lammek 1 , Anna Kwiatkowska 1 , Dariusz Sobolewski 1 ,Lenka Borovičková 2 , Jiřina Slaninová 2 , and Adam Prahl 11 Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland; 2 Institute of OrganicChemistry and Biochemistry, Academy of Sciences of the Czech Republic,Prague, Czech RepublicIntroductionAbout 55 years ago du Vigneaud and his co-workers elucidated the primary structure ofAVP and also worked out its synthesis [1]. Since then, analogues of AVP have attractedN H 2COOHFig. 1. Strucure of (S)-2-(1-adamantyl)glycine.considerable attention and have been investigated frommany points of view [2-4]. A number of highly interestingstudies have been undertaken in an attempt to determine thestructure-activity relationship. The data obtained frompharmacological evaluation of hundreds of AVP analoguesprovided a fairly good understanding of this correlation.It is generally accepted that conformation of theN-terminal part of neurohypophyseal hormone analogues isimportant for their pharmacological activity. In this study wepresent the synthesis and some pharmacological activities offive new analogues of AVP, [Mpa 1 ]AVP (Mpa = 3-mercaptopropionicacid), [Val 4 ]AVP, [D-Arg 8 ]VP and [Mpa 1 , D-Arg 8 ]VP, carrying at position 2 a conformationally constrainednon-proteinogenic alpha-amino acid, (S)-1-adamantyl-glycine (Adg) (Figure 1). Itshould be noticed that the modification, apart from reducing the flexibility, also changedthe character of the molecule from aromatic to aliphatic.Results and DiscussionThe five new analogues of AVP (I-V) were synthesized by Fmoc strategy, purified andcharacterized. The values of the molecular ions were as expected and the purity was higherthan 98%. The activities of the new analogues were determined in the in vitro rat uterotonictest in the absence of magnesium ions, the rat pressor test, and in the antidiuretic assay onconscious rats (for details concerning all tests, see ref. [5]). The results of pharmacologicalevaluation of peptides I-V, together with relevant data for AVP and some related peptides,are presented in Table 1. None of these new analogues exhibited either pressor or antivasopressoractivity. Peptides I and III-V modified at position 2 with Adg showed weakoxytocic agonism (values ranging from 0.20 to 1.90 IU/mg), whereas compound II was aweak oxytocic antagonist. As regards antidiuretic activity, peptides I-III and V are weakagonists, with the exception of analogue IV which possesses moderate antidiureticproperties.It is hypothesized that the bulky planar side chain of the modified molecule togetherwith its aliphatic character are responsible for an almost complete loss of activity of theanalogues. On the basis of these results, we are now undertaking further SAR studies usingNMR and theoretical molecular modelling methodology.432