Combined dose-ratio analysis of cholecystokinin receptor antagonists, devazepide, lorglumide and loxiglumide in the guinea-pig gall bladder.
1. Interactions between cholecystokinin octapeptide (CCK-8) and CCKA-receptor antagonists derived from benzodiazepines (devazepide) and glutamic acid (lorglumide and loxiglumide) have been examined in an improved bioassay using the guinea-pig, isolated, gall bladder preparation. 2. The presence of CCKB-receptors in the assay was provisionally-ruled out on the basis of the low potency of pentagastrin in the assay. By applying analyses of both agonism and antagonism, pentagastrin was shown to behave as a partial agonist at the CCKA-receptor. 3. Devazepide, lorglumide and loxiglumide behaved as simple competitive antagonists of CCKA-receptors and pKB values of 9.98, 7.59 and 7.07 were estimated, respectively. 4. Application of a combined dose-ratio analysis to the interactions between CCK-8 and combinations of devazepide/lorglumide and devazepide/loxiglumide indicated that these molecules behave as syntopic, competitive, antagonists at the CCKA-receptor. 5. We conclude that the guinea-pig gall bladder assay contains a homogeneous population of CCKA-receptors and offer an explanation for the differences between our results and those obtained recently by Maubach et al. (1991) which were taken as preliminary evidence for CCKA-receptor heterogeneity.
Bishop
L A
LA
Department of Analytical Pharmacology, King's College School of Medicine & Dentistry, Rayne Institute, London.
Gerskowitch
V P
VP
Hull
R A
RA
Shankley
N P
NP
Black
J W
JW
D000704:Analysis of Variance; D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D001681:Biological Assay; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D005704:Gallbladder / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D009130:Muscle, Smooth / Q000187:drug effects; D010418:Pentagastrin / Q000378:metabolism / Q000494:pharmacology; D011377:Proglumide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000378:metabolism / Q000494:pharmacology
D001570:Benzodiazepinones; D011949:Receptors, Cholecystokinin; C053737:loxiglumide; D002766:Cholecystokinin; D010418:Pentagastrin; D011377:Proglumide; D020109:Devazepide; C048181:lorglumide; D012844:Sincalide