A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260

doi:10.1016/0014-2999(89)90290-2

European Journal of Pharmacology

Volume 162, Issue 2, 21 March 1989, Pages 273-280

https://doi.org/10.1016/0014-2999(89)90290-2 Get rights and content

Abstract

L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N′ -(3-methylphenyl)urea), interacted in a stereoselective and competitive manner with guinea pig stomach gastrin and brain cholecystokinin (CCK) receptors. The affinity of L-365,260 for both gastrin (K_i = 1.9 nM) and brain CCK-B (K_i = 2.0 nM) receptors was > 2 orders of magnitude higher than its affinity for peripheral pancreatic CCK-A receptors or various other receptors. L-365,260 exhibited a similar high affinity for brain CCK-B receptors of rats, mice and man. A somewhat lower affinity for gastrin and brain CCK-B (IC₅₀ = 20–40 nM) receptors was observed in dog tissues. In vivo, oral administration of L-365,260 antagonized gastrin-stimulated acid secretion in mice (ED₅₀ = 0.03 mg/kg), rats (ED₅₀ = 0.9 mg/kg) and guinea pigs (ED₅₀ = 5.1 mg/kg). L-365,260 did not affect basal acid secretion and did not antagonize histamine- or carbachol-stimulated acid secretion in mice. L-365,260 represents a potentially powerful new tool for investigating gastrin and brain CCK-B receptors, and possibly their role in physiology and disease.

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A list of CCK receptor antagonists can be found in Table 8.3. There are three groups of antagonists for the CCK receptors: amino acid derivatives, for example, benotript and proglumide; peptide analogs of CCK and gastrin, such as JMV-180 and JMV-179135,136 (both antagonize the CCK1 receptor); and nonpeptide ligands, such as members of the benzodiazepine-derivative family, for example, L364,718 (MK-329), an antagonist for the CCK1 receptor,34,125 and L365,260, an antagonist for the CCK2 receptor.128 The activation of CCK receptors involves several pathways.
Cholecystokinin (CCK) is a hormone secreted by the I-cells of the upper small intestine in response to fat, protein, and some nonnutrients, for example, camostat, and a peptide/neurotransmitter secreted by neurons of the central and peripheral nervous systems. There are multiple molecular forms of CCK, for example, CCK-8, CCK-33, and CCK-58, with an active site located within the first eight amino acids of the carboxyl terminus and with a sulfate group on the seventh tyrosine residue. Physiologically, CCK increases pancreatic secretions and gallbladder and smooth muscle contractions as well as inhibits gastric emptying and food intake. CCK evokes these responses by activating two G protein-coupled receptors: CCK₁ and CCK₂. CCK₁ receptors are located mainly in the alimentary tract and contain two affinity states, high and low, whereas CCK₂ receptors are found mainly in the brain. Although a CCK-mediated reduction in cumulative food intake occurs by the activation of low-affinity CCK₁ receptors located on vagal afferents, the vagus, and the splanchnic nerves are necessary for the reduction of meal size (MS) and the prolongation of the inter-meal interval (IMI) by CCK. Finally, the reduction of food intake by CCK occurs by three possible modes of action: paracrine, endocrine, and neurocrine; thus far, the data favor a paracrine mode. In addition, the gut, which is the main source of peripheral CCK, contains the first neuronal component that senses the presence of food, the enteric nervous system. The enteric nervous system may have a role in the reduction of MS and the prolongation of the IMI by CCK.
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European Journal of Pharmacology

Abstract

References (19)

Cholecystokinin in the central nervous system: A minireview

Neuropeptides

Characterization of [³H]pentagastrin binding in guinea pig gastric glands - an alternative convenient ligand for receptor binding assay

Biochem. Biophys. Res. Commun.

A new simple mouse model for the in-vivo evaluation of cholecystokinin (CCK) antagonists: comparative potencies and durations of action of nonpeptide antagonists

Life Sci.

CCK receptors are structurally distinct from pancreas CCK receptors

Biochem. Biophys. Res. Commun.

Benzodiazepine gastrin and cholecystokinin receptor ligands: L-365,260

J. Med. Chem.

Biochemical and pharmacological characterization of a new extremely potent and selective nonpeptide cholecystokinin antagonist

A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus Alliaceus

Science

Gastrin

Clin. Invest. Med.

Design of potent, orally effective nonpeptidal antagonists of the peptide hormone cholecystokinin

Cited by (406)

Biological behavior of 1, 4-benzodiazepines and 1, 4-benzothiazepines

Design and synthesis of novel 1,4-benzodiazepine surrogates as potential CCKA and CCKB antagonists via palladium-catalyzed three-component cascade reactions

The role of cholecystokinin receptors in the short-term control of food intake

Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y

Molecular basis for binding and subtype selectivity of 1,4-benzodiazepine antagonist ligands of the cholecystokinin receptor

Synthesis and structure-activity relationship of new 1,5-dialkyl-1,5- benzodiazepines as cholecystokinin-2 receptor antagonists