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

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Abstract
The Bo-containing amino acid carboranylalanine (Car) was used for replacing the Ph residues of bradykinin (BK), des-Arg9-BK and octa (4-11)-substance P (octa (4-11)-SP), to determine how the increased size and hydrophobicity of the aromatic residues will affect the biological activities [rabbit mesenteric vein and thoracic aorta, guinea pig and cat ileum, and rat blood pressure] of these peptides. Analog 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) were practically inactive. A similar marked reduction of activity was observed with [Car8]-des-Arg9-BK, while [Car5]-des-Arg9-BK, although less potent than the natural BK fragment, showed a prolonged duration of action. Car was also 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 was added at the N-terminal of this sequence for further improvement of the affinity of the antagonism. The 2 chemical modifications did not produce the expected additive change of biological activity but a potent long-acting antagonist was obtained with [Lys1,Car6,Leu9]-des-Arg10-BK. Car is evidently 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.