Role of the C-Terminal Carboxylate in Angiotensin II Activity: Alcohol, Ketone, and Ester Analogues of Angiotensin II

[Ac-Asn¹,Val⁵]angiotensin II analogues containing a C-terminal alcohol (Phe-ol), methyl ketone (Pmk), methyl ester (Phe-OMe), or a-methyl methyl ester (Phe(aMe)-OMe) were prepared in order to examine the relative importance of COOH-mediated ionic vs. hydrogen bonding interactions in angiotensin activities. Based on the observation that only [Ac-Asn¹,Phe-OMe⁸]All (All, angiotensin II) had significant activities (20% oxytocic and 13% pressor) in the rat, with all other analogues having negligible agonistic and antagonistic effects, it is concluded that ionic interaction of the C-terminal carboxylate with the receptor is necessary for angiotensin binding and that hydrogen bonding has little effect. Thus, the different potencies observed for the All methyl ester and for various C-terminal analogues previously reported may simply reflect their relative abilities to generate the active carboxylate species in situ.