Conformation-based design of two cyclic physalaemin analogues.
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.
Medicinal Chemistry Department, University of Sherbrooke, Canada.
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Hölzemann
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Jonczyk
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Eiermann
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Pachler
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Barnickel
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Regoli
D000595:Amino Acid Sequence; D000818:Animals; D004285:Dogs; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010803:Physalaemin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D013696:Temperature
D010803:Physalaemin