Biological activities of kinins and substance P octapeptides (4–11) in which phenylalanine residues have been replaced with L-carboranylalanine

Abstract

The boron-containing amino acid carboranylalanine (Car) has been used for replacing the phenylalanine residues of bradykinin (BK), des-Arg9-BK and octa (4–11)-substance P (octa (4–11)-SP), in order to determine how the increased size and hydrophobicity of the aromatic residues will affect the biological activities of these peptides. Analogues of BK and of octa (4–11)-SP containing Car instead of Phe in positions 5 and 8 (BK) or 7 and 8 (octa (4–11)-SP) are practically inactive. A similar marked reduction of activity is observed with [Car8]-des-Arg9-BK, while [Car5]-des-Arg9-BK, although less potent than the natural BK fragment, shows a prolonged duration of action. Car has also been used to replace Phe5 in combination with the substitution of Phe8 by a Leu in the sequence des-Arg9-BK, in order to prolong the duration of action of antagonists for the B1 receptor of kinins. Moreover, a Lys has been added at the N-terminal of this sequence for further improving the affinity of the antagonism. The two chemical modifications have not produced the expected additive change of biological activity but a potent long-acting antagonist has been obtained with [Lys1,Car6,Leu9]-des-Arg10-BK.It is concluded that Car is unsuitable for replacing the phenyl residues of BK and octa (4–11)-SP, and also Phe8 of the fragment sequence des-Arg9-BK; Car appears, however, to be of some utility when used to replace Phe5 of the same sequence, as it prolongs the duration of action of agonists and of antagonists acting on the B1 receptor for kinins.