An investigation of angiotensin II agonist and antagonist analogues with 5,5-dimethylthiazolidine-4-carboxylic acid and other constrained amino acids.
To probe the receptor-bound conformational requirements of angiotensin II (ANG II) octapeptide agonists and antagonists, the synthesis and biological activities of [Sar1]ANG II agonist and [Sar1,X8]ANG II antagonist analogues (X8 = Ile, D-Phe, or Aib) bearing conformational constraints in positions 3, 5, and 7 were investigated and compared with previous literature efforts. The conformational constraints that were examined include Pro, Dtc (5,5-dimethylthiazolidine-4-carboxylic acid), Aib, Cle, (NMe)Ala, (NMe)Ile, and the lactam modification, L,L-lactam-Phe, previously described by Freidinger et al. (J. Org. Chem. 1982, 47, 104-109). Both [Sar1,(NMe)Ala3 and Pro3]ANG II retained agonist activity, while only [Sar1,(NMe)Ala3,Ile8]ANG II retained antagonist activity. [Sar1,Dtc5]ANG II displayed superior agonist activity, while both [Sar1,Dtc5 and Cle5,Ile8] ANG II displayed superior antagonist activity. In contrast to position 5, Dtc7 substitution for Pro7 of either [Sar1]ANG II or [Sar1,Ile8]ANG II gave analogues with reduced activities. These results are consistent with the hypothesis that conformations of [Sar1]ANG II and [Sar1,Ile8]ANG II containing a C7 conformation in position 7 are preferred for both ANG II agonist and antagonist activity. Incorporation of the L,L-lactam-Phe modification into [Sar1]ANG II gives a pure ANG II antagonist (pA2 8.3), comparable to saralasin (pA2 8.6). In positions 3, 5, and 7 the conformational requirements for the ANG II agonist [Sar1]ANG II and the ANG II antagonist [Sar1,Ile8]ANG II may be different. Individual substitution of (NMe)Ala3, Dtc5, D-Phe8 and Aib8 [[Sar1,Aib8]ANG II: Khosla et al. J. Med. Chem. 1977, 20, 1051-1055] into [Sar1,Ile8]ANG II gives analogues that retain antagonist activity. Multiple substitutions of these types of residues into [Sar1,Ile8]ANG II gives analogue 45 [Sar1,(NMe)Ala3,Dtc5,Aib8]ANG II, 46 [Sar1(NMe)Ala3,D-Phe8]AII, and 47 [Sar1,Dtc5,D-Phe8]AII, which display considerably reduced antagonist activity. In ANG II antagonists the construction of highly constrained analogues may not be possible by the additive substitution of "preferred" constrained amino acids into a single analogue.
Samanen
J
J
Department of Peptidomimetic Research, Smith Kline Beecham Pharmaceuticals, Research and Development, King of Prussia, Pennsylvania 19406-0939.
Cash
T
T
Narindray
D
D
Brandeis
E
E
Adams
W
W
Weideman
H
H
Yellin
T
T
Regoli
D
D
D000596:Amino Acids / Q000737:chemistry*; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry; D007769:Lactams / Q000737:chemistry; D011487:Protein Conformation; D012504:Saralasin / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
D000596:Amino Acids; D007769:Lactams; D013844:Thiazoles; D000804:Angiotensin II; C065579:5,5-dimethylthiazolidine-4-carboxylic acid; D012504:Saralasin