Pharmacological profile of TP‐680, a new cholecystokinin_A receptor antagonist

Abstract

1 The pharmacological characteristics of a newly developed serine derivative (R)-1- [3-(3-carboxypyr-idine-2-yl)thio-2-(indol-2-yl)carbonylamino]propionyl-4-diphenylmethyl-piperazine suppressed the maximal responses of CCK-8-induced amylase release in a concentration-dependent fashion, indicating that TP-680 is an unsurmountable antagonist. 5Repeated 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 Our results indicate that TP-680 is a potent and the most selective CCKA receptor antagonist for the pancreas reported to date.

Pharmacologic Profile of TS-941, a New Benzodiazepine Derivative Cholecystokinin-Receptor Antagonist, in In Vitro Isolated Rat Pancreatic Acini

“…It is possible, therefore, that TS-941 might have some influences not only on the receptor sites in the plasma membrane but also on the cellular mechanisms related to stimulussecretion coupling in response to the subsequent CCK-8 stimulation. In support of this view, but in contrast to our previous observation with serine derivative CCKreceptor antagonist TP-680 (27), addition of loxiglumide, a well-characterized hydrophilic CCK-A-receptor antagonist that rapidly binds to and dissociates from the CCK-A receptor (24), together with TS-941, was unable to protect CCK receptors from the persistent residual antagonism by TS-94 1 (unpublished observation). These results indicate that the reversibility of the antagonism exerted by CCK-receptor antagonists are complex interactions between CCK receptor and CCK-receptor antagonists.…”

“…These differences in the reversibility of the CCK-receptor antagonists appear to be related to the inhibitory potency of the antagonists because FK480 is just as potent as devazepide and 17 and 23 times more potent than TP-680 and TS-941, respectively, which are 106 and 50 times, respectively, more potent than loxiglumide (24,25,27, and this study). However, we found no significant changes in the sensitivity and the responsiveness to CCK-8 stimulation in the acini that were preincubated with 1.0 pM loxiglumide (250 times the I&) for 30 min (unpublished observation).…”

“…Devazepide, FK480, and TP-680 are also known to cause residual inhibition (25)(26)(27), whereas loxiglumide, lorglumide, and tomoglumide do not exert irreversible antagonism (24,28). These differences in the reversibility of the CCK-receptor antagonists appear to be related to the inhibitory potency of the antagonists because FK480 is just as potent as devazepide and 17 and 23 times more potent than TP-680 and TS-941, respectively, which are 106 and 50 times, respectively, more potent than loxiglumide (24,25,27, and this study).…”

Cholecystokinin antagonists: Pharmacological and therapeutic potential

“…This antagonist was approximately 17-fold less potent than devazepide, but 106- fold more potent than loxiglumide in inhibiting the CCK-8-stimulated amylase release from rat pancreatic acini. 278 TP-680 by intravenous administration in mice has shown long-lasting antagonistic properties on CCK-8-stimulated pancreatic secretion, gastric emptying, and gall bladder contraction. The selectivity for these activities was gastric emptying > pancreatic secretion > gall bladder contraction.…”

Pharmacological Study of IQM-97,423, a Potent and Selective CCK₁ Receptor Antagonist with Protective Effect in Experimental Acute Pancreatitis

“…More recently, the pharmacological characteristics of the more selective CCK 1 receptor antagonists TP-680 [21], T-0632 [22], IQM-95,333 [23] and SR146131 [24,25] have been reported. Although these compounds have provided valuable information on the role of CCK 1 receptors, they have some limitations in their use as therapeutic agents.…”