An Investigation of Angiotensin II Agonist and Antagonist Analogues with 5,5-Dimethylthiazolidine-4-carboxylic Acid and Other Constrained Amino Acids

Article abstract of DOI:10.1021/jm00114a012

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.