1. Pharmacological profile of TP-680, a new cholecystokininA receptor antagonist
- Author
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Mitsuyoshi Yamamoto, Makoto Otsuki, Yoshihide Hirohata, Issei Tachibana, Hisashi Shirohara, and Toshiharu Akiyama
- Subjects
Male ,medicine.medical_specialty ,Proglumide ,medicine.drug_class ,Devazepide ,In Vitro Techniques ,Biology ,Binding, Competitive ,Niacin ,Cholecystokinin receptor ,Sincalide ,Internal medicine ,medicine ,Animals ,Cysteine ,Rats, Wistar ,Receptor ,Pancreas ,Cholecystokinin ,Cerebral Cortex ,Pharmacology ,Benzodiazepinones ,Antagonist ,Intracellular Membranes ,Receptor antagonist ,Rats ,Receptor, Cholecystokinin A ,Endocrinology ,Amylases ,Receptors, Cholecystokinin ,Antagonism ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,medicine.drug - Abstract
1. The pharmacological characteristics of a newly developed serine derivative (R)-1-[3-(3-carboxypyridine-2-yl) thio-2-(indol-2-yl)carbonylamino]propionyl-4-diphenylmethyl- piperazine (TP-680), a cholecystokinin type A (CCKA) receptor antagonist, were studied and compared with those of MK-329 and loxiglumide. 2. TP-680 showed approximately 2 and 22 times greater selectivity for peripheral CCKA receptors relative to brain CCK (CCKB) receptors than MK-329 and loxiglumide, respectively, when IC50 values for inhibition of [125I]-CCK-8 binding in isolated acini and cerebral cortex were compared. 3. TP-680 was approximately 17 times less potent than MK-329, but was 106 times more potent than loxiglumide in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. The antagonism produced by TP-680 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. 4. TP-680 caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase release as did MK-329 and loxiglumide. However, in contrast to MK-329 and loxiglumide, TP-680 suppressed the maximal responses of CCK-8-induced amylase release in a concentration-dependent fashion, indicating that TP-680 is an unsurmountable antagonist. 5. Repeated washing of acini after a 30 min treatment with TP-680 restored the responsiveness but not the sensitivity, causing a residual inhibition on the action of CCK-8. 6. The addition of loxiglumide prior to or together with application of TP-680 protected CCK receptors from unsurmountable and irreversible antagonism by TP-680. 7. Our results indicate that TP-680 is a potent and the most selective CCKA receptor antagonist for the pancreas reported to date.
- Published
- 1996