THE AGGREGATION PROPERTIES OF SOME BRADYKININ ANALOGS

Bradykinin (BK) is a peptide hormone with sequence Arg1-Pro2-Pro3-Gly4 -Phe5-Ser6-Pro7-Phe8-Arg9 and has been implicated in a multitude of pa thophysiological processes such as the ability to lower systemic blood pressure and stimulate pain. Bulky, beta-branched D-aliphatic residue s at position 7 combined with bulky L-aliphatic residues at position 8 have now been observed to yield strong antagonists. Nuclear magnetic resonance studies have been carried out on many of these molecules wit h a view to determining their solution conformations. However, two suc h analogs, namely DArg-[Hyp3, Thi5, DSer, DCpg7, Cpg8]-BK [I] and DArg -[Hyp3 , DSer6, DCpg7, Cpg8]-BK [II] (Cpg = alpha-cyclopentyl-glycine; Hyp = 4-hydroxy-L-proline, Thi = beta-(2-thienyl)-L-alanine), have ex hibited an abnormal, non-linear temperature dependence for the amide N H proton of Cpg8. The NH of Arg9 also shows a slightly non-linear temp erature dependence at higher temperatures above 25-degrees-C. In addit ion, a very slow exchange rate for the NH protons of DCpg7, Cpg8 and A rg9 indicated aggregation of these two analogs, which was confirmed us ing the circular dichroism experiments.