Effect of 3-5 monocyclizations of angiotensin II and 4-aminoPhe6-Ang II on AT2 receptor affinity.
The endogenous angiotensin II (Ang II) and the synthetic AT(2) selective agonist 4-aminoPhe(6)-Ang II respond very differently to identical cyclizations. Cyclizations of Ang II by thioacetalization, involving the 3 and 5 amino acid residue side chains, provided ligands with almost equipotent binding affinities to Ang II at the AT(2) receptor. In contrast, the same cyclization procedures applied on the AT(2) selective 4-aminoPhe(6)-Ang II delivered significantly less potent AT(2) receptor ligands, although the AT(2)/AT(1) selectivity was still very high. The fact that different structure-activity relationships are observed after imposing conformational restrictions on Ang II and 4-aminoPhe(6)-Ang II, respectively, suggests that the peptides, despite large similarities might adopt quite different backbone conformations when binding to the AT(2) receptor.
Lindman
Susanna
S
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Lindeberg
Gunnar
G
Frändberg
Per-Anders
PA
Nyberg
Fred
F
Karlén
Anders
A
Hallberg
Anders
A
D000804:Angiotensin II / Q000819:agonists / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D003500:Cyclization; D005260:Female; D008024:Ligands; D008099:Liver / Q000737:chemistry; D008968:Molecular Conformation; D010649:Phenylalanine / Q000031:analogs & derivatives*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine; D014599:Uterus / Q000737:chemistry
D008024:Ligands; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C009722:4-aminophenylalanine; D010649:Phenylalanine