Synthesis of potent antagonists of substance P by modifying the methionyl and glutaminyl residues of its C-terminal hexapeptide and without using D-amino acids.
Analogues of [Orn6]-SP6-11 have been synthesized in which the Met11-NH2 residue is replaced by the alpha, gamma-dimethyl, alpha, gamma-dibenzyl and alpha, gamma-di-tert-butyl esters of glutamic acid. These analogues were tested in three in vitro preparations representative of NK-1, NK-2 and NK-3 receptor types for agonist and antagonist activity. The dimethyl analogue is a selective full agonist in the NK-1 receptor type and a weak antagonist in the other two receptor types, while the dibenzyl and the di-tert-butyl analogues are potent antagonists in the NK-1 receptor type and weak antagonists in the other two receptor types. It is concluded that appropriate modification at the alpha-carboxamide and the side chain of the methionine residue of substance P may induce antagonism without using D-amino acids.
Manolopoulou
A
A
Department of Chemistry, University of Patras, Greece.
Karagiannis
K
K
Stavropoulos
G
G
Poulos
C
C
Jordan
C C
CC
Hagan
R M
RM
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D003106:Colon / Q000187:drug effects; D005971:Glutamates / Q000737:chemistry*; D018698:Glutamic Acid; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008715:Methionine / Q000737:chemistry*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D018039:Receptors, Tachykinin; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000596:Amino Acids; D005971:Glutamates; D009842:Oligopeptides; D010446:Peptide Fragments; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; C079225:substance P (6-11), Orn(6)-; D013373:Substance P; D018698:Glutamic Acid; D008715:Methionine