In vitro activity and selectivity of glucosidic SP(6-11) analogues.
The relative potencies of a series of substance P (6-11) analogues have been determined for spasmogenic activity in the guinea pig ileum in vitro and for potentiation of electrically evoked contractions in the rat vas deferens in vitro. ED50 values were determined for the new analogues. Substance P and its methyl ester were used as standard agonists. Substitution of Gly9 by Pro on [Glu6]SP(6-11) increased four times the activity on the NK-1 receptor. The glycosilation of [Glu6]SP(6-11) by the incorporation of a beta-D-glucopyranosyl amide residue on the gamma-carboxyl group of Glu6 reduced both the activity and selectivity. The simultaneous substitution of Gly9 by Pro and the incorporation of a monosaccharide moiety on the gamma-carboxyl of Glu6 on [Glu6]SP(6-11) yielded an analogue with 60-fold enhanced selectivity relative to substance P for the NK-1 receptor. These results may indicate that the critical factor providing potency to SP(6-11) analogues is mostly related to conformational rather than hydrophilicity aspects of the molecular structure.
Haro
I
I
Biological Organic Chemistry Department, Jordi Girona Salgado, Barcelona, Spain.
Ruiz
P
P
Valencia
G
G
García-Antón
J M
JM
Reig
F
F
Rodriguez
R E
RE
D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects*
D010446:Peptide Fragments; C060758:substance P (6-11), Glu(6)-; D013373:Substance P