A selective AT2 receptor ligand with a gamma-turn-like mimetic replacing the amino acid residues 4-5 of angiotensin II.
Three angiotensin II (Ang II) analogues encompassing a benzodiazepine-based gamma-turn-like scaffold have been synthesized. Evaluation of the compounds in a radioligand binding assay showed that they had no affinity to the rat liver AT(1) receptor. However, one of the compounds displayed considerable affinity to the pig uterus AT(2) receptor (K(i) = 3.0 nM) while the other two lacked affinity to this receptor. It was hypothesized that the reason for the inactivity of one of these analogues to the AT(2) receptor was that the guanidino group of the Arg(2) residue and/or the N-terminal end of the pseudopeptide could not interact optimally with the receptor. To investigate this hypothesis, a conformational analysis was performed and a comparison was carried out with the monocyclic methylenedithioether analogue cyclo(S-CH(2)-S)[Cys(3,5)]Ang II which is known to bind with high affinity to the AT(2) receptor (K(i) = 0.62 nM). This comparison showed that, in the compounds with high AT(2) receptor affinity, the guanidino group of the Arg(2) residue and the N-terminal end could access common regions of space that were not accessible to the inactive compound. To examine the importance of the guanidino group for binding, the Arg side chain was removed by substituting Arg(2) for Ala(2) in the analogue having the high affinity. This analogue lacked affinity to AT(2) receptors, which supports the role of the guanidino group in receptor binding.
Rosenström
Ulrika
U
Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Box 574, Uppsala University, 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 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008566:Membranes; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009215:Myometrium / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine
D007093:Imidazoles; D008024:Ligands; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D001569:Benzodiazepines