Synthesis of new substance P analogues releasing histamine from rat peritoneal mast cells

Article abstract of DOI:10.1016/0223-5234(92)90025-V

New analogues of the N-terminal fragment of substance P [Arg-Pro-Lys-Pro, SP(1-4)] were synthesized and their activities on histamine release from rat peritoneal mast cells were compared. The potency of these compounds decreases in the following order (in abbreviation): SP(1-4)C₁₂ > C'₁₂-SP(1-4)-OCH₃ > C'₁₂-SP(1-4)-OH, H-Lys-Pro-C₁₂ and SP. Benzalkonium chloride, a competitive antagonist of peptide-induced histamine release from rat mast cells, inhibits the effect of SP and SP analogues with IC₅₀ in the range of micromolar concentrations. SP(1-4)-C₁₂ and C'₁₂-SP(1-4)-OCH₃ have been found to be 10-fold more active than SP on the GTPase activity of purified G proteins (G(o)/G(i)). The lack of clear structural relationships for agonist activities supports a receptor-less mechanism for histamine release by SP and its analogs. This effect could be elicited by a direct stimulation of G proteins.