Synthesis of a potent agonist of substance P by modifying the methionyl and glutaminyl residues of the C-terminal hexapeptide of substance P. Structure-activity relationships.
Analogues of [Orn6]-SP6-11 have been synthesized in which the Met11 residue is replaced by glutamate gamma-alkylesters. These analogues were tested in three in vitro preparations representative of NK-1, NK-2, and NK-3 receptor types. Substitution of the SCH3 group of the Met11 side chain by a COOR (R = methyl, ethyl, n-propyl, n-butyl, cyclohexyl) group results in analogues which are full agonists in NK-1 and NK-2 preparations but show little agonist activity in the NK-3 preparation. When the SCH3 group is replaced by a t-butyl ester group and the resulting analogue is a full agonist in all the above preparations and more active than the parent hexapeptide and SP-OCH3 at NK-1 receptors. It is concluded that for activity at NK-1 receptors methionine can be replaced by gamma-t-butyl glutamate without loss of activity, whilst at NK-2 and NK-3 receptors the above substitution increases the activity of [Orn6]-SP6-11. Other gamma-alkyl esters of the glutamic acid reduce its biological activity.
Karagiannis
K
K
Department of Chemistry, University of Patras, Greece.
Manolopoulou
A
A
Stavropoulos
G
G
Poulos
C
C
Jordan
C C
CC
Hagan
R M
RM
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D003106:Colon / Q000502:physiology; D005973:Glutamine / Q000031:analogs & derivatives; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D008715:Methionine / Q000031:analogs & derivatives; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*; D011169:Portal Vein / Q000502:physiology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D013329:Structure-Activity Relationship; D013373:Substance P / Q000737:chemistry / Q000502:physiology*
D010446:Peptide Fragments; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D005973:Glutamine; D013373:Substance P; C032292:substance P (6-11); D008715:Methionine; D011761:Pyrrolidonecarboxylic Acid