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Pharmacological profile of TP‐680, a new cholecystokinin A receptor antagonist
Author(s) -
Akiyama Toshiharu,
Tachibana Issei,
Hirohata Yoshihide,
Shirohara Hisashi,
Yamamoto Mitsuyoshi,
Otsuki Makoto
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15321.x
Subject(s) - cholecystokinin receptor , cholecystokinin , endocrinology , medicine , chemistry , proglumide , receptor , antagonist , ritanserin , receptor antagonist , biology
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 (CCK A ) 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 CCK A receptors relative to brain CCK (CCK B ) receptors than MK‐329 and loxiglumide, respectively, when IC 50 values for inhibition of [ 125 I]‐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 CCK A receptor antagonist for the pancreas reported to date.