ABSTRACT
The discovery of the non-peptide angiotensin II (Ang II) receptor antagonists and molecular characterization of the Ang n receptor subtypes are major achievements in the past decade that markedly increa ed our under tanding of the renin-angioten in ystem. The foundations for these di coverie were laid over everal decade through exten ive empirical explorations of the structure-activity relation hip of Ang II analogue . The e studies demon trated: the importance of Ang II-conformation that place carboxy-terminal phenylalanine (Phe8) and po ition 4 tyrosine (Tyr4) ide chain in an 'agoni t conformation' (appropriate modification of either residue could switch the function of the molecule from agonist to antagoni t) , and the ignificant liabilitie a ociated with peptide and emi-peptide antagoni ts that limited their therapeutic value. All such analogue retained ignificant partial agoni t activity, rendering them u ele a antihyperten ive agents. The discovery of the non-peptide Ang II antagoni t , hence, was a major breakthrough. But the functional pharmacophore defined by the structure-function of Ang II helped rationalize the mode of action of the non-peptide antagoni t and also led to rational development of potent derivative , which are in clinical trial now. The current tructural hypothe i i that diver e non-peptide antagoni t pre ent nearly the ame
three-dimen ional pharmacophoric point a Ang II doe to the receptor, enabling them to competitively di place Ang II at the receptor binding ite. The non-peptide tructure mimic the contact made by the agoni t ide chain of Ang II , while the partial agoni t activity exhibited by the peptide antagonist i absent in non-peptide .
