Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT1 and AT2 receptors.
A benzodiazepine-based beta-turn mimetic has been designed, synthesized, and incorporated into angiotensin II. Comparison of the mimetic with beta-turns in crystallized proteins showed that it most closely resembles a type II beta-turn. The compounds exhibited high to moderate binding affinity for the AT2 receptor, and one also displayed high affinity for the AT1 receptor. Molecular modeling showed that the high-affinity compounds could be incorporated into a previously derived model of AT2 receptor ligands.
Rosenström
Ulrika
U
Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
Sköld
Christian
C
Lindeberg
Gunnar
G
Botros
Milad
M
Nyberg
Fred
F
Karlén
Anders
A
Hallberg
Anders
A
D000804:Angiotensin II / Q000737:chemistry*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D066298:In Vitro Techniques; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000737:chemistry*; 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; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D008024:Ligands; D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D001569:Benzodiazepines