Synthesis and biological activities of substance P antagonists

Abstract

Several substance P analogues containing various D-amino acid modifications have been synthesized by the solid-phase procedure, detached from the solid support by ammonolysis, and purified by gel filtration combined with reversed-phase chromatography. Three compounds were fair to very potent competitive antagonists of substance P on three bioassays, i.e., guinea pig ileum, rabbit mesenteric vein, and guinea pig trachea. [Arg6,D-Trp10]SP(6-11) is a reasonable antagonist in all three bioassays and [D-Pro4,D-Trp7,9]SP(4-11) is a very potent competitive antagonist with pA2 values ranging around 6.0.

Neuropeptides Activate Human Mast Cell Degranulation and Chemokine Production

“…SP-P-T has the same amino acid sequence as SP but has two modified D amino acids (see Table 2) and is an effective inhibitor in vivo. 45,46 Although spantide I is also an effective inhibitor of SP effects in vivo, it is unclear if these are caused by mast cell activation. 47,48 Our studies also showed that the first three C-terminus amino acids of SP (Arg-Pro-Lys) are unimportant for its activity on human mast cells because SP lacking these amino acids was still able to activate human mast cell degranulation (Fig.…”

The Importance of Amino Acid and Peptide Chemistry in the Treatment of the Major Diseases: Neuropeptides

“…Also some substance P derivatives that contain Damino acids e.g. [Arg 6 , D-Trp l0 ]-sp (6)(7)(8)(9)(10)(11) and [Pro 4 , D-Trp 7.9 ]-sp (4-11) act as strongly competitive antagonists [47]. Stavropoulos, George et al [48], synthesized potent agonists of substance P. The analogues [Glp 6 , Glu(OBzl) 11 ]-sp(6-l 1) figure ( 4) and [Glp 5 , Glu(OBzl) 11 ] -SP-(5-l 1) figure (5) of the c-terminal hexapeptide and heptapeptide as shown in figures (4,5).…”

“…Jirina et al [100] synthesized different analogues of arginine-vasopressin which has the formula, figure (47). Vasopressin is released into the brain in a circadian rhythm by neurons of the suprachmiasmatic nucleus [105].…”

Analogs of substance P. Peptides containing D-amino acid residues in various positions of substance P and displaying agonist or receptor selective antagonist effects

“…Met"]-SP-OMe (10) [JV"-Z-Arg1,Al<-Z-Lys3,D-Val7'8,D-Metn]-SP-OMe (11) [(V"-Z-ArgI,Al*-Z-Lys3,D-Val1,8,D-Metu]-SP (12) [7V"-Z-Arg1,lV'-Z-Lys3,D-Phe910]-SP-OMe ( 13)…”

“…In our search for SP antagonists, the available structure-activity information on all the tachykinin analogues was taken into consideration, and this led us to divide the SP molecule into two parts-an N-terminal (1)(2)(3)(4)(5)(6) region and a C-terminal (7)(8)(9)(10)(11) region. Major structural changes in the N-terminal region do not result in serious losses of biological activity.…”