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.
Hölzemann
G
G
Medicinal Chemistry Department, University of Sherbrooke, Canada.
Jonczyk
A
A
Eiermann
V
V
Pachler
K G
KG
Barnickel
G
G
Regoli
D
D
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