51833-69-3Relevant academic research and scientific papers
Angiotensin II analogues with sulphur-containing side-chains in position 5. A structure-activity relationship study
Perodin, Jacqueline,Bouley, Richard,Escher, Emanuel,Assimomytis, Nick,Magafa, Vassiliki,Manessi-Zoupa, Evy,Theodoropoulos, Dimitrios,Cordopatis, Paul
, p. 526 - 529 (2007/10/03)
Four sets of angiotensin II (AngII) analogues with position 5 modifications, two agonist series with either Asp or Sar in position 1 and L- Phe in position 8, and two antagonist series with again Asp or Sar in position I and Leu in position 8 were synthesized. Modifications in positions 5 were introduced successively: Ile, Nle, Met, S-ethyl Cys, S-n-propyl-Cys, S-n-butyl Cys, S-t-butyl Cys and S-benzyl Cys in all four series. The study was undertaken in order to investigate the 5-position residue of AngII by replacing the hydrophobic side-chain by another containing an electrophilic moiety. The analogues were synthesised by solid phase synthesis using the Boc/Bzl or Fmoc/But strategy. All analogues were evaluated by their binding properties to the AT1 receptor on bovine adrenocortical membranes (bAT1). The results indicate that AngII analogues bind, irrespective of their agonistic or antagonistic nature or of their position 1 modification, in a similar manner and that position 5 modifications without β-branching behave in an additive manner towards their affinity.
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.
