Pharmacological characterisation of a new potent and specific nonpolypeptidic cholecystokinin antagonist.
D,L-4-(3,4-Dichloro-benzoylamino)-5-(N-3-methoxypropyl- pentylamino)-5-oxo-pentanoic acid (CR 1505) belongs to a newly discovered class of agents with cholecystokinin (CCK) antagonistic activity. CR 1505 displaces CCK-8 from the central CCK receptors at concentrations of 9.1 mumol/l, and from the peripheral CCK receptors at concentrations of 0.33 mumol/l. CR 1505 antagonizes in vitro the contractant effects of CCK-8 on gall bladder strips of the guinea pig at 0.79 mumol/l and those on the small intestine at 1.6 mumol/l. These antagonistic effects are dose dependent and of competitive type. The antagonistic activities of CR 1505 against contractions of smooth muscles elicited by CCK-8 are at least 1000 times more potent than those against the contractions elicited by acetylcholine, BaCl2, histamine, serotonin, Substance P, bradykinin or dimethylphenylpiperazine. CR 1505 is also practically ineffective against the contractions of the small intestine of the guinea pig elicited by electrical field stimulations either as "cholinergic twich" (0.05 Hz), or as "cholinergic contractions" (trains of 10 min at 1 Hz), or as "non-cholinergic contractions" (200 impulses at 5 Hz in presence of atropine). CR 1505 is therefore a potent, specific, competitive and reversible CCK antagonist.
Setnikar
I
I
Rotta Research Laboratorium, Monza/Milano, Italy.
Bani
M
M
Cereda
R
R
Chisté
R
R
Makovec
F
F
Pacini
M A
MA
Revel
L
L
Rovati
L C
LC
Rovati
L A
LA
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D002766:Cholecystokinin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005260:Female; D005704:Gallbladder / Q000187:drug effects; D005973:Glutamine / Q000031:analogs & derivatives*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D010179:Pancreas / Q000378:metabolism; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism; D013045:Species Specificity
D011949:Receptors, Cholecystokinin; D005973:Glutamine; C053737:loxiglumide; D002766:Cholecystokinin; D011377:Proglumide