Effect of covalent dimer conjugates of angiotensin II on receptor affinity and activity in vitro.
Angiotensin II [1-8 or 2-8] analogues and [4-8] fragments were dimerized through the amino- or carboxy-terminal groups in order to try to increase their potency as reported for other hormones. The binding affinity to the angiotensin II receptor subtypes A (A IIA) and B (A IIB) was tested and compared to the potency in rabbit aortic ring. The [2-8] dimers coupled through the N-terminus show no significant change in potency in aortic ring. The [4-8] fragments coupled through the N-terminus are inactive in the ring. They have however a significantly increased affinity for the A IIA receptor, the specific function of which has not yet been reported. When angiotensin II analogues or fragments are coupled through the C-terminus, there was a significant drop in affinity and potency, confirming the importance of the free carboxyl group in position 8 for binding and activity. It is concluded that binding to the A IIB receptor correlates well with the effectiveness in aortic ring. However, in contrast to the beneficial effect reported for a large number of other hormones, dimerization of angiotensin II or its fragments is not accompanied by an increased biological activity in aortic ring.
de Gasparo
M
M
Research Department, Ciba-Geigy Limited, Basle, Switzerland.
Whitebread
S
S
Kamber
B
B
Criscione
L
L
Thomann
H
H
Riniker
B
B
Andreatta
R
R
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D011817:Rabbits; D011945:Receptors, Angiotensin / Q000187:drug effects*
D010446:Peptide Fragments; D011945:Receptors, Angiotensin; D000804:Angiotensin II