Angiotensin II pseudopeptides containing 1,3,5-trisubstituted benzene scaffolds with high AT2 receptor affinity.
Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as gamma-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a K(i) of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (K(i) = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as gamma-turn mimics.
Georgsson
Jennie
J
Department of Medicinal Chemistry, Division of Organic Pharmaceutical Chemistry, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
Sköld
Christian
C
Plouffe
Bianca
B
Lindeberg
Gunnar
G
Botros
Milad
M
Larhed
Mats
M
Nyberg
Fred
F
Gallo-Payet
Nicole
N
Gogoll
Adolf
A
Karlén
Anders
A
Hallberg
Anders
A
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D066298:In Vitro Techniques; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009215:Myometrium / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism; D013552:Swine
D001555:Benzene Derivatives; D008024:Ligands; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II