Effect of three nonpeptide cholecystokinin antagonists on human isolated gallbladder.
Cholecystokinin is the most important stimulant of postprandial gallbladder contraction, and a regulator of gallbladder fasting tone. The aim of this study was to evaluate the effect of dexloxiglumide on isolated human gallbladder contraction induced by cholecystokinin-octapeptide and to compare this effect to that of lorglumide and amiglumide, two glutaramic acid analogs of dexloxiglumide. The negative logarithms of the antagonist dissociation constant (pK(B)) values were 7.00 +/- 0.14, 6.95 +/- 0.11, and 6.71 +/- 0.10 for lorglumide, dexloxiglumide, and amiglumide, respectively. Dexloxiglumide produced a concentration-dependent rightward shift of the cholecystokinin-octapeptide curve, without affecting its maximal response. A similar effect was obtained both with lorglumide and amiglumide. Moreover, the slopes for the three antagonists did not differ significantly from unity. These data show that the three molecules have a potent antagonistic effect, of a competitive nature, on gallbladder cholecystokinin type 1 receptors. It may be concluded that dexloxiglumide, lorglumide, and amiglumide exhibit a promising therapeutic profile for biliary colic and other gastrointestinal disorders in which CCK1 receptors play important physiological roles.
Maselli
M A
MA
Experimental Pathophysiology and Pharmacology Laboratory, Scientific Institute of Gastroenterology S. de Bellis, Castellana Grotte, Bari, Italy.
Piepoli
A L
AL
Pezzolla
F
F
Guerra
V
V
Caruso
M L
ML
Mennuni
L
L
Lorusso
D
D
Makovec
F
F
D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D005704:Gallbladder / Q000187:drug effects*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010421:Pentanoic Acids / Q000494:pharmacology*; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology*
D006727:Hormone Antagonists; D010421:Pentanoic Acids; C103490:dexloxiglumide; D002766:Cholecystokinin; D011377:Proglumide; C048181:lorglumide