Conformation-based design of two cyclic physalaemin analogues

✍ Scribed by Günter Hölzemann; Alfred Jonczyk; Volker Eiermann; Klaus C. R. Pachler; Gerhard Barnickel; Domenico Regoli

• Book ID: 102765865
• Publisher: Wiley (John Wiley & Sons)
• Year: 1991
• Tongue: English
• Weight: 526 KB
• Volume: 31
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/bip.360310614

✦ Synopsis

Two new cyclic analogues of physalaemin were designed on the basis of the conformation found in DMSO solution. Glp-Ala-cyclo ( -Asp-Pro-Asn-Lys-) -Phe-Tyr-Gly-Leu-Met-NH2

( 1 ) was synthesized by cyclization of physalaemin. In 2 the Asp residue was replaced by Glu. The linear analogue of 2 was synthesized by the solid phase method and subsequently cyclized. Two-dimensional nmr methods were employed to assign the proton and carbon resonances. Proton-proton distances were extracted from rotating frame nuclear Overhauser effect spectra and used as restraints in the molecular dynamics calculations. Analogue 1 was found to have a similar conformation as physalaemin, whereas 2 did not form intramolecular hydrogen bonds. The pharmacological evaluation revealed that both peptides have similar potencies as physalaemin in the dog carotid artery (NK-1 receptor). Therefore, the charged side chains of physalaemin appear not essential for NK-1 activation. However, the other tachykinin receptors show good sensitivity to the cyclic peptides. It is concluded that the replacement of a salt bridge by an amide bond connecting the side chains of natural residues might provide useful information about the biological significance of some charged side chains of neurokinins.