Short pseudopeptides containing turn scaffolds with high AT2 receptor affinity.
Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT2 receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT2 receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT2 receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT2 receptor affinity in truncated Ang II analogues.
Georgsson
Jennie
J
Department of Medicinal Chemistry, Division of Organic Pharmaceutical Chemistry, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden.
Rosenström
Ulrika
U
Wallinder
Charlotta
C
Beaudry
Hélène
H
Plouffe
Bianca
B
Lindeberg
Gunnar
G
Botros
Milad
M
Nyberg
Fred
F
Karlén
Anders
A
Gallo-Payet
Nicole
N
Hallberg
Anders
A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009215:Myometrium / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013552:Swine
D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2