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

Wei Jun Zhang, Gregory V. Nikiforovich, Jacqueline Pérodin, Darren E. Richard, Emanuel Escher, Garland R. Marshall

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23 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2738-2744
Number of pages7
JournalJournal of Medicinal Chemistry
Volume39
Issue number14
DOIs
StatePublished - Jul 5 1996

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