Synthesis of potent agonists of substance P by replacement of Met11 with Glu(OBzl) and N-terminal glutamine with Glp of the C-terminal hexapeptide and heptapeptide of substance P.
The analogues [Glp6,Glu(OBzl)11]SP(6-11) and [Glp5,Glu(OBzl)11]SP(5-11) of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the N-terminal glutamine has been replaced by pyroglutamic acid, while the COOCH2C6H5 ester group has replaced the SCH3 group of the Met11 side chain. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD) and rat portal vein (RPV). The results showed that both analogues are highly potent and selective agonists on GPI through the NK-1 receptor. They are more potent than SP itself, with 1.54 and 1.25 respective values of relative potency on GPI. Their selectivity has been studied by utilizing atropine-treated guinea pig ileum (GPI+At). The analogues showed low activity on RVD and RPV tissues, which represent NK-2 and NK-3 monoreceptor assay, respectively.
Stavropoulos
G
G
Department of Chemistry, University of Patras, Greece.
Karagiannis
K
K
Anagnostides
S
S
Ministrouski
I
I
Selinger
Z
Z
Chorev
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D005973:Glutamine / Q000737:chemistry*; D006168:Guinea Pigs; D008715:Methionine / Q000737:chemistry*; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry* / Q000031:analogs & derivatives; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000032:analysis; D018041:Receptors, Neurokinin-2 / Q000032:analysis; D018042:Receptors, Neurokinin-3 / Q000032:analysis; D013373:Substance P / Q000819:agonists* / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D009842:Oligopeptides; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C095956:substance P (5-11), Glp(5)-Glu(O-benzyl)(11)-; C095955:substance P (6-11), Glp(6)-Glu(O-benzyl)(11)-; D005973:Glutamine; D013373:Substance P; D008715:Methionine; D011761:Pyrrolidonecarboxylic Acid