A pseudopeptide that is a potent cholecystokinin agonist in the peripheral system is able to inhibit the dopamine-like effects of cholecystokinin in the striatum.
There are no known specific effective cholecystokinin (CCK) receptor antagonists of both peripheral and central nervous systems. Here, we describe experiments which demonstrate that a synthetic pseudopeptide analogue of CCK-7 is a potent agonist in the peripheral system and behaves as a selective and highly potent inhibitor of the dopamine-like effects of CCK in the striatum. This compound, t-butyloxycarbonyl-Tyr (SO3H)-Nle psi (COCH2)Gly-Trp-Nle-Asp-Phe-NH2, is able to stimulate enzyme secretion from rat pancreatic acini, with high efficacy and potency. It is also very potent in inhibiting the binding of labeled CCK-8 to rat pancreatic acini (IC50 = 5 nM) and to guinea pig and mouse brain membranes (IC50 = 0.7 nM). However, this compound is able to antagonize the effects of intrastriatally injected t-butyloxycarbonyl-[Nle28,31] CCK-8 in mice, with high potency.
Mendre
C
C
Centre de Pharmacologie-Endocrinologie, Montpellier, France.
Rodriquez
M
M
Gueudet
C
C
Lignon
M F
MF
Galas
M C
MC
Laur
J
J
Worms
P
P
Martinez
J
J
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism*; D012844:Sincalide / Q000378:metabolism*; D013045:Species Specificity; D013329:Structure-Activity Relationship
D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin; D012844:Sincalide; D004298:Dopamine