37827-06-8Relevant articles and documents
An Investigation of Angiotensin II Agonist and Antagonist Analogues with 5,5-Dimethylthiazolidine-4-carboxylic Acid and Other Constrained Amino Acids
Samanen, J.,Cash, T.,Narindray, D.,Brandeis, E.,Adams, W.,et al.
, p. 3036 - 3043 (2007/10/02)
The probe the receptor-bound conformational requirements of angiotensin II (ANG II) octapeptide and antagonists, the synthesis and biological activities of 1>ANG II agonist and 1,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, previouslydescribed by Freidinger et al. (J.Org.Chem. 1982, 47, 104-109).Both 1,(NMe)Ala3, and Pro3>ANG II retained agonist activity, while only 1,(NMe)Ala3,Ile8>ANG II retained antagonistic activity. 1,Dtc5>ANG II displayed superior agonist activity, while both 1,Dtc5 and Cle5,Ile8>ANG II displayed superior antagonist activity. In contrast to position 5, Dtc7 substitution for Pro7 of either 1>ANG II or 1,Ile8>ANGII gave analogues with reduced activities.These results are consistent with the hypothesis that confirmations of 1>ANG II and 1,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 1>ANG II gives a pure ANG antagonist (pA2 8.3), comparable to saralasin pA2 8.6).In position 3, 5, and 7 the conformational requirements for the ANG IIagonist 1>ANG II and the ANG II antagonist 1,Ile8>ANG II may be different.Individual substitution of (NMe)Ala3, Dtc5, D-Phe8 and Aib8 1,Aib8>ANG II: Kosla et al.J.Med.Chem. 1972, 20, 1051-1055> into 1,Ile8>ANG II gives that retain antagonistic activity.Multiple substitutions of these types of residues into 1,Ile8>ANG II gives analogue 45 1,(NMe)Ala3,Dtc5,Aib8>ANG II, 46 1(NMe)Ala3,D-Phe8>AII, and 47 1,Dtc5,D-Phe8>AII, which display considerably reduced antagonist activity.In ANG II antagonist the construction of highly constrained analogues may not be possible by the additive substitution of "preferred" constrained amino acids into a single analogue.
Structure-Activity Relationships for the Competitive Angiotensin Antagonist 1,O-methyltyrosine4>angiotensin II (Sarmesin)
Goghari, Mahesh H.,Franklin, Kevin J.,Moore, Graham J.
, p. 1121 - 1124 (2007/10/02)
Analogues of the competitive angiotensin antagonist 1,Tyr(Me)4>ANG II (sarmesin) in which the sarcosine-1, O-methyltyrosine-4, and phenylalanine-8 residues were modified have been synthesized by the solid-phase method.The agonist and antagonist potencies of the 23 peptides synthesized were determined in the rat isolated uterus assay.At position 1, replacement of Sar with Asp, Ala, or Pro gave inactive analogues, and deletion of the N-terminal amino acid produced inactive heptapeptides for all analogues investigated.At position 4, substitution of Tyr with Tyr(Et), D-Tyr, D-Phe, Ile, Thr, or Hyp resulted in inactive analogues, whereas substitution of Phe gave a potent competitive antagonist (pA2 = 7.9), which retained significant agonist activity (22percent).For position 8, 1,Tyr(Me)4,Ile8>ANG II and 1,Phe4,Ile8>ANG II were weaker antagonists (pA2 = 6.6 and 6.7, respectively) than 1,Ile8>ANG II (pA2 apparent = 8,1) and moreover, were reversible competitive antagonists.These findings demonstrate that the structural requirements for receptor blockade by sarmesin are remarkably stringent-modifications at positions 1, 4, and 8 markedly reduce the antagonist activity of this peptide.
