A novel, quantitative bio-assay for cholecystokinin type-1 receptor activity in the anaesthetised rat

Freedman, Jamie; Barrett, Terrance D.; Shankley, Nigel P.

doi:10.1016/j.vascn.2005.09.002

Cited by 2 publications

(5 citation statements)

References 7 publications

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“…One possible explanation is tachyphylaxis to CCK‐A stimulation. In isolated rat duodenum, continuous CCK‐A stimulation led to rapid development of tachyphylaxis to its contractile response 22 . The fact that gastrointestinal side effects with GI181771X treatment occurred throughout the duration of the trial is evidence against complete tachyphylaxis to CCK‐A‐mediated responses.…”

Section: Discussionmentioning

confidence: 99%

“…In isolated rat duodenum, continuous CCK-A stimulation led to rapid development of tachyphylaxis to its contractile response. 22 The fact that gastrointestinal side effects with GI181771X treatment occurred throughout the duration of the trial is evidence against complete tachyphylaxis to CCK-A-mediated responses. Another, more likely explanation for lack of weight reduction with GI181771X treatment is that alternative weight-regulating pathways negated the selective change in CCK-A activity.…”

Section: Discussionmentioning

confidence: 99%

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Stimulation of Cholecystokinin-A Receptors With GI181771X does not Cause Weight Loss in Overweight or Obese Patients

Jordan

Greenway

Leiter

et al. 2007

Clin Pharmacol Ther

104

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Cholecystokinin (CCK) decreases meal size through activation of CCK-A receptors on vagal afferents. We tested the hypothesis that the selective CCK-A agonist GI181771X induces weight loss in obese patients. Patients with body mass index > or = 30 or > or = 27 kg/m2 with concomitant risk factors were randomized to 24-week, double-blind treatment with different GI181771X doses or matching placebo together with a hypocaloric diet. The primary efficacy end point was the absolute change in body weight. To monitor pancreatic and gallbladder effects, patients underwent abdominal ultrasound and magnetic resonance imaging before and after treatment. We randomized 701 patients to double-blind treatment. GI181771X did not reduce body weight and had no effect on waist circumference or other cardiometabolic risk markers. Gastrointestinal side effects were more common with GI181771X than with placebo treatment, whereas hepatobiliary or pancreatic abnormalities did not occur. CCK-A by itself does not have a central role in long-term energy balance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Stimulation of Cholecystokinin-A Receptors With GI181771X does not Cause Weight Loss in Overweight or Obese Patients

Jordan

Greenway

Leiter

et al. 2007

Clin Pharmacol Ther

104

View full text Add to dashboard Cite

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“…The potency of JNJ-17156516 and dexloxiglumide was assessed in anesthetized rats using a newly developed model (Freedman et al, 2006). In brief, male Sprague-Dawley rats (170 -340 g) were anesthetized with 1 to 3% isoflurane in room air, and the jugular vein and carotid artery were cannulated to allow intravenous infusion of CCK-8S and measurement of blood pressure, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The contractile response of the duodenum to continuous infusion of CCK-8S exhibited tachyphylaxis; therefore, a protocol was developed in which a 1-nmol kg Ϫ1 dose of CCK-8S was administered as a 1-min infusion through the jugular vein at 10-min intervals (Freedman et al, 2006). This resulted in a stable response to CCK-8S, and it was quantified by measuring the number of high-amplitude contractions (HACs), defined as an increase Ͼ5 mm Hg over baseline.…”

Section: Methodsmentioning

confidence: 99%

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3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516), a Novel, Potent, and Selective Cholecystokinin 1 Receptor Antagonist: In Vitro and in Vivo Pharmacological Comparison with Dexloxiglumide

Morton

Barrett²,

Yan³

et al. 2007

J Pharmacol Exp Ther

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3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516) is a novel, potent, and selective cholecystokinin (CCK)1-receptor antagonist. In this study, the pharmacology of JNJ-17156516 was investigated both in vitro and in vivo, and the pharmacokinetic profile was evaluated in rats. JNJ-17156516 expressed high-affinity at the cloned human (pK I ϭ 7.96 Ϯ 0.11), rat (pK I ϭ 8.02 Ϯ 0.11), and canine (pK I ϭ 7.98 Ϯ 0.04) CCK1 receptors, and it was also highly selective for the CCK1 receptor compared with the CCK2 receptor across the same species (ϳ160-, ϳ230-, and ϳ75-fold, respectively). The high affinity of JNJ-17156516 at CCK1 receptors in vitro was confirmed in radioligand binding studies on fresh human gallbladder tissue (pK I ϭ 8.22 Ϯ 0.05). In a functional in vitro assay of guinea pig gallbladder contraction, JNJ-17156516 behaved as a competitive antagonist, with a pK B value of 8.00 Ϯ 0.07. In vivo, JNJ-17156516 produced a parallel, rightward shift in the CCK-8S-evoked contraction of the guinea pig gallbladder. The dose required to shift the CCK-8S dose-response curve was 240 nmol kg Ϫ1 i.v. In the anesthetized rat, JNJ-17156516 produced a dose-related decrease in the number of duodenal contractions evoked by infusion of CCK-8S, with an ED 50 ϭ 484 nmol kg Ϫ1 . Pharmacokinetic analysis of JNJ-17156516 in rats, revealed that JNJ-17156516 had a half-life of 3.0 Ϯ 0.5 h and a very high bioavailability (108 Ϯ 10%) in this species. Overall, we have demonstrated that JNJ-17156516 is a high-affinity selective human CCK1 receptor antagonist with good pharmacokinetic properties in rats.

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A novel, quantitative bio-assay for cholecystokinin type-1 receptor activity in the anaesthetised rat

Cited by 2 publications

References 7 publications

Stimulation of Cholecystokinin-A Receptors With GI181771X does not Cause Weight Loss in Overweight or Obese Patients

Stimulation of Cholecystokinin-A Receptors With GI181771X does not Cause Weight Loss in Overweight or Obese Patients

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516), a Novel, Potent, and Selective Cholecystokinin 1 Receptor Antagonist: In Vitro and in Vivo Pharmacological Comparison with Dexloxiglumide

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