Structure-activity studies on the C-terminal amide of substance P

Abstract

Twelve C-terminal heptapeptide analogs of substance P [SP] were synthesized by solid phase and by the classical solution method. The modifications all concerned the C-terminal primary amide of SP and should help to understand the biological significance of this carboxamide, as evaluated by in vivo and in vitro bioassays [guinea pig ileum and rat blood pressure]. Not the slightest change of the 2 amide protons is tolerated without an important loss of activity: replacement of 1 or 2 amide protons with alkyl groups, extension of the amide to the hydrazide and its alkyl analogs and exchange of the amide with an ester or a carboxylic acid all reduce the relative activity/affinity by at least 2-fold. It is not clear for what reason all these modifications produce such a drastic activity reduction.