AT2-selective angiotensin II analogues containing tyrosine-functionalized 5,5-bicyclic thiazabicycloalkane dipeptide mimetics.
This paper reports the synthesis of two angiotensin II analogues with tyrosine-functionalized 5,5-bicyclic thiazabicycloalkane dipeptide mimetics replacing the Tyr(4)-Ile(5) residues. The preparation of these analogues relies on the synthesis and incorporation of an alpha,alpha-disubstituted chimeric amino acid derivative and on-resin bicyclization to a cysteine residue. The synthesized analogues both displayed high angiotensin AT(2)/AT(1) receptor binding preferences and had AT(2) receptor affinities in the same low nanomolar range as angiotensin II itself. Conformational analysis, using experimental constraints derived from NMR studies, indicated that the Tyr(4) and His(6) residues in one of the angiotensin II analogues were in close proximity to each other.
Johannesson
Petra
P
Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
Erdélyi
Máté
M
Lindeberg
Gunnar
G
Frändberg
Per-Anders
PA
Nyberg
Fred
F
Karlén
Anders
A
Hallberg
Anders
A
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047248:Crown Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004121:Dimethyl Sulfoxide; D004151:Dipeptides / Q000737:chemistry*; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D011869:Radioligand Assay; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012996:Solutions; D013329:Structure-Activity Relationship; D013552:Swine; D014443:Tyrosine / Q000737:chemistry*; D014599:Uterus / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D047248:Crown Compounds; D004151:Dipeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012996:Solutions; D000804:Angiotensin II; D014443:Tyrosine; D004121:Dimethyl Sulfoxide