Angiotensin II analogues. 14. Roles of the imidazole nitrogens of position-6 histidine in pressor activity

Article abstract of DOI:10.1021/jm00196a010

Replacement of the position-6 histidine residue in [Asn¹,Ile⁵]angiotensin II produced analogues with pressor activities in the rat (compared to [Asn¹,Val⁵]angiotensin II = 100%) as follows: 2,4-diaminobutyric acid, 0.02%; 4-nitrophenylalanine, 0.02%; 4-aminophenylalanine, 0.05%; β-(2-imidazolyl)-L-α-alanine, 0.4%; β-(2-imidazolyl)-D-α-alanine, 0.04%; β-(2-pyridyl)-D-α-alanine, 3.5%; β-(2-pyridyl)-D-α-alanine, 0.1%. ]Asn¹,Tyr(3-Bzl)⁴,Ile⁵,Phe(4-NO₂)⁶]AII was isolated as a side produce in the HF-deprotection reaction and it was shown to possess 0.03%, pressor activity. Extensive racemization (78%) of butyloxycarbonyl-β-(2-pyridyl)-L-α-alanine occurred during solid-phase synthesis, despite the use of conditions which minimized racemization of Boc-His(Bzl). The resultant diastereomeric peptides were separated by column chromatography and characterized. Incorportion of the racemic N(α)-butyloxycarbonyl-N(im)-benzyl-β-(2-imidazoyl)-DL-α-alanine into the peptide and separation of the resultant diastereomeric angiotensin II by countercurrent distribution eliminated the need for the laborious resolution and protection of the L isomer, which might racemize extensively during peptide synthesis. Correlation of the chemical structures with biological activities of position-6 analogues suggests that the heterocyclic nitrogens of histidine are important for angiotensin II to be recognized by the receptor, and the pros-pyridine nitrogen of histidine plays a minor role and the tele-pyrrole nitrogen a major role in the interaction. Since β-(2-imidazolyl)alanine (Ima) and β-(2-pyridyl)alanine (Pya) resemble histidine in steric environment and the ability to participate in hydrogen-bonding and nucleophilic interactions, they are generally useful for the study of structure-activity relationships in order to assess the importance of such effects in the molecular events of hormone-receptor interaction. Furthermore, tautomerization of these heterocyclic amino acids does not alter the spatial alignment of their heterocyclic nitrogens relative to the peptide backbone. Consequently, replacement of histidine by Ima and Pya can unambiguously delineate the roles of the pros and tele nitrogens of histidine in other biologically important peptides.