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<BBR RID="jm9507744b00001">-Arg²<BBR RID="jm9507744b00002">-Val³<BBR RID="jm9507744b00003">-Tyr⁴<BBR RID="jm9507744b00004">-Val/Ile⁵<BBR RID="jm9507744b00005">-His⁶<BBR RID="jm9507744b00006">-Pro⁷<BBR RID="jm9507744b00007">-Phe⁸<BBR RID="jm9507744b00008">, 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 <BO>(3)</BO>, Sar¹-Arg²-Val³-Tyr⁴-cyclo(Asp⁵-His⁶-Apt⁷)-Phe⁸ <BO>(4)</BO>, Sar¹-Arg²-Val³-Tyr⁴-cyclo(Glu⁵-His⁶-Apt⁷)-Phe⁸ <BO>(5)</BO>, Sar¹-Arg²-Val³-Tyr⁴-cyclo(Cys⁵-His⁶-Mpt⁷)-Phe⁸ <BO>(6)</BO>, Sar¹-Arg²-Val³-Tyr⁴-cyclo(Cys⁵-His⁶-Mpc⁷)-Phe⁸ <BO>(7)</BO>, Sar¹-Arg²-Val³-Tyr⁴-cyclo(Hcy⁵-His⁶-Mpt⁷)-Phe⁸ <BO>(8)</BO>, and Sar¹-Arg²-Val³-Tyr⁴-cyclo(Hcy⁵-His⁶-Mpc⁷)-Phe⁸ <BO>(9)</BO>, where Apt stands for 4-amino-trans-proline, and Mpt and Mpc for 4-mercapto-trans- and -cis-prolines, respectively. Compound <BO>(9)</BO> showed good affinity at AT-1 receptors, namely a K<INF>D</INF> = 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 <BO>9</BO> are due to interaction with AT-1 receptor of only two functionally important groups, namely, the side chains of the His⁶ and Phe⁸ residues.