New selective AT2 receptor ligands encompassing a gamma-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists.
New benzodiazepine-based gamma-turn mimetics with one or two amino acid side chains were synthesized. The gamma-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val(3)-Tyr(4)-Ile(5) or Tyr(4)-Ile(5) peptide segments. All of the resulting pseudopeptides displayed high AT(2)/AT(1) receptor selectivity and exhibited AT(2) receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT(2) receptor could position important structural elements in common areas. A previously described benzodiazepine-based gamma-turn mimetic with high affinity for the AT(2) receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT(2) receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44(mapk), and suppress proliferation of PC12 cells.
Rosenström
Ulrika
U
Department of Medicinal Chemistry, BMC, Uppsala University, Sweden.
Sköld
Christian
C
Plouffe
Bianca
B
Beaudry
Hélène
H
Lindeberg
Gunnar
G
Botros
Milad
M
Nyberg
Fred
F
Wolf
Gunter
G
Karlén
Anders
A
Gallo-Payet
Nicole
N
Hallberg
Anders
A
D019943:Amino Acid Substitution; D000804:Angiotensin II / Q000737:chemistry*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000737:chemistry; D013552:Swine
D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D001569:Benzodiazepines; C073402:PD 123319; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3