Full agonists of CCK8 containing a nonhydrolyzable sulfated tyrosine residue.
The sulfate ester of CCK26-33 or CCK8 (Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2) borne by the tyrosine residue is a critical determinant of the biological activity of this peptide. In order to increase the stability of this molecule, the sulfated tyrosine has been replaced by a synthetic amino acid (L,D)Phe(p-CH2SO3Na) in which the OSO3H group was replaced by the nonhydrolyzable CH2SO3H group. Both isomers were separated by chromatography and the stereochemistry of the Phe(p-CH2SO3Na) residue in each peptide was established by NMR spectroscopy. The biological activities of the new derivatives Ac[X27, Nle28,Nle31]CCK27-33 were compared with those of Boc[Nle28,Nle31]CCK27-33, an equiactive analogue of CCK8 and Boc[D-Tyr(SO3Na)27,Nle28,Nle31]CCK27-33. Besides their highly enhanced chemical stability, Ac[L-Phe(p-CH2SO3Na)27,Nle28,Nle31]CCK27-33 and Ac[D-Phe(p-CH2SO3Na)27,Nle28,Nle31]CCK27-33 display high affinity for peripheral and central CCK receptors (KI congruent to 10(-9) M) and proved to be full agonists in the stimulation of pancreatic secretion as well as in the in vitro CCK8-induced contractions of the guinea pig ileum.
Marseigne
I
I
Département de Chimie Organique, U 266 INSERM, UA 498 CNRS, Paris, France.
Roy
P
P
Dor
A
A
Durieux
C
C
Pélaprat
D
D
Reibaud
M
M
Blanchard
J C
JC
Roques
B P
BP
D000681:Amylases / Q000378:metabolism; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D012844:Sincalide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013431:Sulfates; D014443:Tyrosine
D013431:Sulfates; D014443:Tyrosine; D000681:Amylases; D012844:Sincalide