NOVEL CYCLIC ANALOGS OF ANGIOTENSIN-II WITH CYCLIZATION BETWEEN POSITION-5 AND POSITION-7 - CONFORMATIONAL AND BIOLOGICAL IMPLICATIONS

To study the conformational features of molecular recognition of angio tensin II (2)-Val(3)-Tyr(4)-Val/Ile(5)-His(6)-Pro(7)-Phe(8), ALI), the synthesis and biological testing of several cyclic analogs of AII cyc lized between positions 5 and 7 have been performed. The synthesized a nalogs were )-Val(3)-Tyr(4)-cyclo(Cys(5)-His(6)-Pen(7))-Phe(8) (3), )- Val(3)-Tyr(4)-cyclo(Asp(5)-His(6)-Apt(7))-Phe(8) (4), )-Val(3)-Tyr(4)- cyclo(Glu(5)-His(6)-Apt(7))-Phe(8) (5), )-Val(3)-Tyr(4)-cyclo(Cys(5)-H is(6)-Mpt(7))-Phe(8) (6), )-Arg(2)-Val(3)-Tyr(4)-cyclo(Cys(5)-His(6)-M pc(7)) (7), )-Val(3)-Tyr(4)-cyclo(Hcy(5)-His(6)-Mpt(7))-Phe(8) (8), an d )-Val(3)-Tyr(4)-cyclo(Hcy(5)-His(6)-Mpc(7))-Phe(8) (9), where Apt st ands for 4-amino-trans-proline, and Mpt and Mpc for 4-mercapto-trans- and -cis-prolines, respectively. Compound (9) showed goad affinity at AT-1 receptors, namely a K-D = 20 nM. In functional assays, it showed the characteristics of a weak partial agonist with a relative affinity of 0.26% of that for AII and an intrinsic efficacy, alpha E, of 0.42. Molecular modeling suggested a possible explanation for this finding: the relatively strong binding and the weak partial agonistic activity of compound 9 are due to interaction with AT-1 receptor of only two f unctionally important groups, namely, the side chains of the His(6) an d Phe(8) residues.