CCK-A receptor inhibitor 1

Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans

Exogenous cholecystokinin (CCK) induces early satiety when infused into humans. Whether alimentary CCK (CCK-A) receptor blockade stimulates food intake in humans is, however, uncertain. The aim of the present investigation was, therefore, to establish the effect of CCK-A receptor blockade on satiety and eating behavior in healthy volunteers. To further explore the role of endogenous CCK, the effects of the specific CCK-A receptor antagonist loxiglumide (Lox; 22 micromol. kg(-1). h(-1)) on satiety and eating behavior were investigated in healthy men and compared with saline infusions (as placebo) in a series of randomized, double-blind, placebo-controlled, crossover studies. Lox produced a slight (7%), but not significant (P = 0.104), increase in food intake that was accompanied by a modest (10%), but significant (P < 0.004), increase in calorie intake. Fluid ingestion was not affected by Lox. Subjects experienced more hunger and delayed fullness during Lox infusion than during saline infusion (P < 0.05). This study provides further evidence that CCK is an endogenous physiological satiety signal acting through CCK-A receptor-mediated mechanisms. Repeated-dose studies comparing hunger and satiety responses after CCK-A receptor blockade in healthy subjects and patients with eating disorders may help clarify the possible involvement of endogenous CCK in these conditions.

Design of concise, scalable route to a cholecystokinin 1 (CCK 1) receptor antagonist

Development of efficient, scalable routes for the synthesis of (S)-3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl propionic acid, a selective cholecystokinin 1 (CCK 1) receptor antagonist, is described. A key feature of the scale-up route is a concise construction of the complete pyrazole framework in a single step by reacting an aryl hydrazine with an elaborated acetylenic ketone. This route was then further refined incorporating efficient enantioselective strategies to obtain the desired S-enantiomer in high optical purity. The first strategy involved an efficient, recyclable, kinetic resolution by enzyme-catalyzed hydrolysis of the racemic ester. In the second-generation route, the requisite stereochemistry at the chiral center was generated at an early stage in the synthesis involving a remarkable diastereoselective addition of inexpensive (S)-(-)-ethyl lactate to an alkylaryl ketene. Both methods furnished optically pure (>99% ee) final drug substance as its crystalline sodium salt.

A cloned CCK-A receptor transduces multiple signals in response to full and partial agonists

Chinese hamster ovary (CHO) cells, stably transfected with the cloned rat CCK-A receptor, were used to study signal transduction events initiated by cholecystokinin octapeptide (CCK-8) and the partial agonist JMV-180. In single CHO-CCK-A cells loaded with fura-2, superfusion of CCK-8 (10 pM-1 nM) resulted in an increase in intracellular Ca2+ concentration ([Ca2+]i). At CCK-8 concentrations < 100 pM, the signal consisted of [Ca2+]i oscillations. At higher concentrations, CCK-8 induced a typical biphasic response consisting of a large peak followed by a lower sustained plateau. Superfusion of JMV-180 also resulted in an increase in [Ca2+]i; in contrast to acinar cells this increase did not consist exclusively of [Ca2+]i oscillations. Both CCK-8 and JMV-180 increased polyphosphoinositide hydrolysis, although JMV-180 stimulated formation of only 10% as much [3H]inositol phosphates. [Ca2+]i signals stimulated by both CCK-8 and JMV-180 were blocked by the aminosteroid U-73122. CCK-8 (1-10 nM) increased formation of adenosine 3',5'-cyclic monophosphate (cAMP) and release of arachidonic acid in CHO-CCK cells. These increases were not mimicked by JMV-180 (10 microM). Furthermore, no cAMP formation or arachidonate release could be detected when cells were incubated with both JMV-180 and CCK-8. These data indicate that in CHO-CCK-A cells, unlike acinar cells, both CCK-8 and JMV-180 increase [Ca2+]i by similar mechanisms. However, the CCK-A receptor can differentially recognize and then activate discrete transduction pathways on binding of these two agonists.

Oral administration of a synthetic trypsin inhibitor increases pancreatic duct function in CCK-A receptor-deficient rats

The effects of oral administration of a synthetic trypsin inhibitor on bicarbonate secretion were examined in cholecystokinin A (CCK-A) receptor-deficient (OLETF) rats and compared with Wistar rats. Rats were fed chow containing 0.1% trypsin inhibitor for 7 days. Rats were prepared with cannulae draining bile and pancreatic juice separately and with duodenal and extrajugular vein cannulae after 3-day trypsin inhibitor ingestion. Then the animals were maintained in Bollman cages, and the experiments were conducted 4 days after surgery. After 1.5 h of basal secretion with bile-pancreatic juice return, bile-pancreatic juice was diverted for 2 h. The responses of bicarbonate secretion to bile-pancreatic juice diversion were significantly enhanced in rats treated with trypsin inhibitor compared with those given a control diet, whereas responses of fluid and protein secretion were not affected in OLETF rats. The response of protein secretion, but not those of fluid or bicarbonate secretion, was enhanced in Wistar rats by treatment with trypsin inhibitor. Carbonic anhydrase II gene expression was increased by 7-day treatment with trypsin inhibitor only in OLETF rats, and not in Wistar rats.

CCK receptor antagonists

1. The peptide hormone and neurotransmitter, cholecystokinin, is widely distributed throughout the gastrointestinal tract and central nervous system and mediates a diverse number of biological functions. 2. Two receptor subtypes, CCK-A and CCK-B, have been identified by both pharmacological characterization and molecular cloning. The CCK-A receptor is the predominant peripheral CCK receptor subtype and the CCK-B receptor is the predominant central CCK receptor. In addition, there are discrete populations of CCK-A receptors in the brain and CCK-B receptors are present in gastric mucosa. 3. Subtype selective antagonists have been developed which discriminate between the two receptor subtypes. One of the major chemical classes has exploited a benzodiazepine template present in asperlicin which was initially discovered in a natural product screen for CCK receptor antagonists. 4. The structurally related benzodiazepines L-365,260, L-740,093, and YM022 are selective antagonists of the CCK-B receptor subtype. Their in vitro pharmacological profiles have been characterized using the human CCK-B receptor expressed in CHO cells. 5. L-365,260 behaves in a manner consistent with that of a competitive antagonist and both L-740,093 and YM022 behave as insurmountable CCK-B receptor antagonists in vitro.