Conformationally Restricted Analogues of Substance P
The three-dim-nsional structure of a peptide deduced from conformational analyses (nuclear magnetic resonance and circular dichroism spectroscopies) and/or from energy calculations should provide an insight into the structural requirements of the binding protein, if this structure has any relevance to the conformation which interacts with the binding protein. A decisive contribution to overcome this problem has been the design of constrained analogues of the peptide which simulate the predicted conformers. Indeed such rigidified analogues, if active, must contribute to a more accurate description of the bioactive conformation[l]. We have established, using NMR and CD spectroscopies, that the three-dimensional structure of SP is strongly influenced by its environment. The main features of the conformation model we have proposed are the flexibility of the N-terminal Arg-ProLys, the a-helical folding of the core of SP, Pro-Gln-Gln-Phe-Phe, and the folding of the C-terminal carboxamide towards the primary amides of Gin5 and Gln6  The validity of this model has been checked by the means of constrained cyclic analogues of SP. Therefore, we have synthesized two groups of disulfide bridged analogues of SP.
KeywordsCyclic Peptide Bioactive Conformation Primary Amide Cyclic Analogue Rigidify Analogue
Unable to display preview. Download preview PDF.
- 3.Nikiforovich GV, Balodis YuYu, Chipens GI (1981) Conformations of SP molecule. In:Brundfeldt K (ed) Peptides 1980, Proceedings of the 16th European Peptide Symposium, Copenhagen: Scriptor, 631–635Google Scholar
- 12.Sandberg BEB (1985) Structure activity relationship for SP: A review; In: Jordan CC and Oehme P (eds) Substance P: Metabolism and Biological actions, pp.65-8l. Taylor and Francis: London and PhiladelphiaGoogle Scholar
- 13.Chassaing G, Convert O, Lavielle S Conformationally analogy between SP and physalaemin. Biochim Biophys Acta (in press)Google Scholar
- 14.Lavielle S, Chassaing G, Julien S, Besseyre J, Marquet A, Beaujouan J-C, Torrens Y, Glowinski J (1986) Influence of the amino acids of SP in the recognition of its receptor: affinities of synthesized SP analogues for the specificl251-BHSP binding site on rat brain synaptosomes.Neuropeptides 7:191–200PubMedCrossRefGoogle Scholar
- 15.Lavielle S, Chassaing G, Julien S, Marquet A, Bergstrom L, Beaujouan J-C, Torrens Y, Glowsinki J (1986) Specific recognition of SP or NKB receptors by analogues of SP substituted at positions 8 and 9. Eur J Pharmacol (in press)Google Scholar