Novel cyclic analogs of angiotensin II with cyclization between positions 5 and 7: Conformational and biological implications

To study the conformational features of molecular recognition of angiotensin II (Asp¹-Arg²-Val³-Tyr⁴-Val/Ile⁵-His⁶-Pro⁷-Phe⁸, AII), the synthesis and biological testing of several cyclic analogs of AII cyclized between positions 5 and 7 have been performed. The synthesized analogs were Sar¹-Arg²-Val³-Tyr⁴-cyclo(Cys⁵-His⁶-Pen⁷)-Phe⁸ (3), Sar¹-Arg²-Val³-Tyr⁴-cyclo(Asp⁵-His⁶-Apt⁷)-Phe⁸ (4), Sar¹-Arg²- Val³-Tyr⁴-cyclo(Glu⁵-His⁶-Apt⁷)-Phe⁸ (5), Sar¹-Arg²-Val³-Tyr⁴- cyclo-(Cys⁵-His⁶-Mpt⁷)-Phe⁸ (6), Sar¹-Arg²-Val³-Tyr⁴-cyclo(Cys⁵- His⁶-Mpc⁷-Phe⁸ (7), Sar¹-Arg²-Val³-Tyr⁴4-cyclo(Hcy⁵-His⁶-Mpt⁷)- Phe⁸ (8), and Sar¹-Arg²-Val³-Tyr⁴-cyclo(Hcy⁵-His⁶-Mpc⁷)-Phe⁸ (9), where Apt stands for 4-amino-trans-proline, and Mpt and Mpc for 4-mercapto- trans- and -cis-prolines, respectively. Compound (9) showed good 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, αE, 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 functionally important groups, namely, the side chains of the His⁶ and Phe⁸ residues.