YM022 [(R)-1-[2,3-dihydro-1(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea]: An irreversible cholecystokinin type-B receptor antagonist

Dunlop, John; Brammer, Neil; Evans, Non; Ennis, Christine

doi:10.1016/s0006-2952(97)00139-1

Cited by 12 publications

(5 citation statements)

References 13 publications

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“…The value of the Schild plot slope was not significantly different from unity, suggesting competitive, surmountable antagonism. This is in agreement with two previous reports ( Nishida et al ., 1994a ; Ding & Håkanson, 1996b ), but in disagreement with a recent report ( Dunlop et al ., 1997 ), in which it was claimed that YM022 acts as an irreversible antagonist in Chinese ovary cells transfected with the human CCK 2 receptor gene. At present, we have no explanation for this discrepancy.…”

Section: Discussioncontrasting

confidence: 69%

Pharmacological analysis of CCK₂ receptor antagonists using isolated rat stomach ECL cells

Lindström

Björkqvist

Håkanson

1999

British J Pharmacology

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1 Gastrin stimulates rat stomach ECL cells to secrete histamine and pacreastatin, a chromogranin A (CGA)-derived peptide. The present report describes the e ect of nine cholecystokinin 2 (CCK 2 ) receptor antagonists and one CCK 1 receptor antagonist on the gastrin-evoked secretion of pancreastatin from isolated ECL cells. 2 The CCK 2 receptor antagonists comprised three benzodiazepine derivatives L-740,093, YM022 and YF476, one ureidoacetamide compound RP73870, one benzimidazole compound JB 93182, one ureidoindoline compound AG041R and three tryptophan dipeptoids PD 134308 (CI988), PD135158 and PD 136450. The CCK 1 receptor antagonist was devazepide. 3 A preparation of well-functioning ECL cells (*80% purity) was prepared from rat oxyntic mucosa using counter-¯ow elutriation. The cells were cultured for 48 h in the presence of 0.1 nM gastrin; they were then washed and incubated with antagonist alone or with various concentrations of antagonist plus 10 nM gastrin (a maximally e ective concentration) for 30 min. Gastrin doseresponse curves were constructed in the absence or presence of increasing concentrations of antagonist. The amount of pancreastatin secreted was determined by radioimmunoassay. 4 The gastrin-evoked secretion of pancreastatin was inhibited in a dose-dependent manner. YM022, AG041R and YF476 had IC 50 values of 0.5, 2.2 and 2.7 nM respectively. L-740,093, JB93182 and RP73870 had IC 50 values of 7.8, 9.3 and 9.8 nM, while PD135158, PD136450 and PD134308 had IC 50 values of 76, 135 and 145 nM. The CCK 1 receptor antagonist devazepide was a poor CCK 2 receptor antagonist with an IC 50 of about 800 nM. 5 YM022, YF476 and AG041R were chosen for further analysis. YM022 and YF476 shifted the gastrin dose-response curve to the right in a manner suggesting competitive antagonism, while the e ects of AG041R could not be explained by simple competitive antagonism. pK B values were 11.3 for YM022, 10.8 for YF476 and the apparent pK B for AG041R was 10.4.

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Section: Discussioncontrasting

confidence: 69%

Pharmacological analysis of CCK₂ receptor antagonists using isolated rat stomach ECL cells

Lindström

Björkqvist

Håkanson

1999

British J Pharmacology

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“…YM022 has shown a higher potency than that of L‐365 260 in several animal bioassays (IC 50 0.0012 μmol L –1 and 2.8 μmol L –1 , respectively), 30 and a selectivity for CCK‐B/gastrin receptors 1000‐fold greater than for the CCK‐A receptor, 31 , 32 whereas the selectivity of L‐365 260 for the CCK‐B receptor was two orders of magnitude higher than for the CCK‐A receptor 29 . YM022 has shown a IC 50 of 7.4 nmol L –1 on a bioassay using the human CCK‐B receptor expressed in CHO cells, 33 and showed a selectivity for the human CCK‐B receptor 6000‐fold greater than the A type 34 . L‐365 260 exhibits a 100‐fold higher affinity for CCK‐B receptors (IC 50 10 nmol L –1 ) than L‐364 718 (IC 50 1 μmol L –1 ) 23 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and molecular characterization of muscular cholecystokinin receptors in the human lower oesophageal sphincter

González

Farré

Monés

et al. 2000

Neurogastroenterology Motil

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In vitro cholecystokinin (CCK) contracts the human lower oesophageal sphincter by stimulating muscular receptors. The aim of this study was to characterize the muscular CCK receptor subtypes in the human lower oesophageal sphincter. Twenty-five circular strips from six patients were studied. RNA was extracted, reverse transcribed, and cDNAs were amplified with primers for human CCK-A and B receptors. The potency of the contraction induced by CCK-8, desulphated CCK-8, and gastrin-I, and the effect of the CCK-A (loxiglumide and SR 27897) and the CCK-B (YM022 and L-365 260) specific receptor antagonists were compared. Both CCK-A and CCK-B receptor mRNAs were found in functional lower oesophageal sphincter strips. The potency of the CCK-8 concentration-dependent contraction was two and three orders of magnitude higher than that of desulphated CCK-8 and gastrin-I, respectively. The CCK-8-induced contraction was blocked by the CCK-A receptor antagonists loxiglumide (IC50 11 micromol L-1) and SR 27897 (IC50 74 nmol L-1) but not by CCK-B receptor antagonists (1 micromol L-1). Our data suggest that, although the human lower oesophageal sphincter expresses both CCK-A and CCK-B receptors, the contractile effect of CCK-8 on the circular muscle is mainly due to the activation of CCK-A receptors.

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“…aldosterone secretion by adrenal cortical cells [19,59], acid secretion by gastric mucosal cells [60] and cell depolarization [61,62]) but also intermediate intracellular events (including inositol phosphate [56,63–67], cGMP [68] and cAMP accumulation [69–71], transient rises of [Ca 2+ ] I [53,72,73] and arachidonate release [74]). Receptor stimulation can also be quantified irrespective of the generated signalling cascade by measuring the rate at which cells acidify their environment with products of their energy metabolism [66,75–77]. Such assays usually fall into two categories: those in which second messenger accumulation is measured over a set time period (‘stop‐time’ assays) and those in which peak levels of a transient response are measured.…”

Section: New Experimental Approachesmentioning

confidence: 99%

New insights in insurmountable antagonism

Vauquelin¹,

Liefde²,

Birzbier³

et al. 2002

Fundamemntal Clinical Pharma

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Antagonists that produce parallel rightward shifts of agonist dose-response curves with no alteration of the maximal response are traditionally classified as surmountable, while insurmountable antagonists also depress the maximal response. Although the longevity of the antagonist-receptor complex is quoted in many studies to explain insurmountable antagonism, slowly interconverting receptor conformations, allosteric binding sites, and receptor internalization have been evoked as alternative explanations. To complicate matters even further, insurmountable antagonism is not only drug-related; it may also depend on the tissue, species and experimental design. For the sake of drug development, it is important to elucidate the molecular mechanisms of insurmountable antagonism. New experimental approaches, such as intact cell studies and the use of computer-assisted simulations based on dynamic receptor models, herald the advent of better insight in the future.

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YM022 [(R)-1-[2,3-dihydro-1(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea]: An irreversible cholecystokinin type-B receptor antagonist

Cited by 12 publications

References 13 publications

Pharmacological analysis of CCK₂ receptor antagonists using isolated rat stomach ECL cells

Pharmacological analysis of CCK₂ receptor antagonists using isolated rat stomach ECL cells

Pharmacological and molecular characterization of muscular cholecystokinin receptors in the human lower oesophageal sphincter

New insights in insurmountable antagonism

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YM022 [(R)-1-[2,3-dihydro-1(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea]: An irreversible cholecystokinin type-B receptor antagonist

Cited by 12 publications

References 13 publications

Pharmacological analysis of CCK2 receptor antagonists using isolated rat stomach ECL cells

Pharmacological analysis of CCK2 receptor antagonists using isolated rat stomach ECL cells

Pharmacological and molecular characterization of muscular cholecystokinin receptors in the human lower oesophageal sphincter

New insights in insurmountable antagonism

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Pharmacological analysis of CCK₂ receptor antagonists using isolated rat stomach ECL cells

Pharmacological analysis of CCK₂ receptor antagonists using isolated rat stomach ECL cells