Development of 1,4-benzodiazepine cholecystokinin type B antagonists

Bock, Mark G.; DiPardo, Robert M.; Evans, B.; Rittle, Kenneth E.; Whitter, Willie L.; Garsky, Victor M.; Gilbert, Kevin F.; Leighton, James L.; Carson, Kenneth L.

doi:10.1021/jm00078a018

Cited by 71 publications

(44 citation statements)

References 10 publications

(31 reference statements)

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“…21,22,23,24 Spacers of varied length ranging from 9 to 22 atoms were employed in order to optimize the length for bridging of these receptors and, in this regard, efforts were focused on 16 to 22 atoms because other reported bivalent ligands that target dimeric opioid receptors are believed to bridge in this range. 25 The mu-opioid-selective agonist pharmacophore was derived from 1 (oxymorphone),26 whereas the CCK 2 antagonist pharmacophore is closely related to 2 (L-365,260) 27. The combination of agonist and antagonist pharmacophores in the bivalent ligand was based on reports that such pharmacologic interaction results in enhancement of analgesia with concomitant loss of tolerance 28,29.…”

Section: Introductionmentioning

confidence: 99%

Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK₂) Receptors by Novel Bivalent Ligands

et al. 2008

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Both mu opioid (MOP) † and type 2 cholecystokinin (CCK 2 ) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK 2 receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK 2 receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing muopioid agonist and CCK 2 receptor antagonist pharmacophores linked through spacers containing 16 to 22 atoms, but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK 2 receptors in vivo.

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Section: Introductionmentioning

confidence: 99%

Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK₂) Receptors by Novel Bivalent Ligands

et al. 2008

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“…This goal was pursued through the incorporation of bulkier substituents at the N-1 position and water-solubilizing groups into the structure of L-365,260. Thus, more potent analogues were obtained either by the introduction of a diethyl acetamide group at N-1 as in 23 154 (Table V), or by saturation of the 5-phenyl substituent to the cyclohexyl in L-708,474 155 (24). However, the water solubility of these compounds was also very low.…”

Section: Cck 2 Receptor Antagonistsmentioning

confidence: 99%

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Herranz

2003

Medicinal Research Reviews

168

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Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK(1) and CCK(2). Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK(1) and CCK(2) antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK(1) and CCK(2) antagonist. CCK(1) antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK(2) antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.

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“…Cholecystokinins (CCKs) are endogenous neuropeptides interacting with G protein-coupled central and peripheral CCK-receptors of which there are at present two subtypes known, i.e., CCK1 = CCKA, mainly situated in the gastrointestinal tract, and CCKz = CCKB, predominantly present in the brain. L-365260, 3R( + )-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N 1 -(3-methylphenyl) urea is a potent CCKz selective antagonist, whereas the selectivity is reversed in the (S)-enantiomer L-365 346, a potent CCKJ antagonist (Table 5) as shown by BOCK et al (1993). It was reported by 1AGERSCHMIDT et al (1996) that histidine His381 of the rat CCKz receptor determines its selectivity for antagonists.…”

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confidence: 92%

Enantioselectivity in Drug-Receptor Interactions

Soudijn¹,

Wijngaarden²,

IJzerman³

2003

Stereochemical Aspects of Drug Action and Disposition

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A. IntroductionG protein-coupled receptors (GPCRs) constitute one of the largest superfamilies of proteins in the human genome. It is estimated that there are at least 600 and probably over 1000 receptor species. The known ones are the target for approximately 60% of today's medicines for such diverse disease states as high blood pressure (,B-adrenoceptor and angiotensin receptor antagonists), asthma (,B-adrenoceptor agonists), and acid overproduction in the stomach (histamine H2 receptor antagonists). Each member shares structural and/or sequence motifs and operates by common transduction mechanisms to mediate the transmission of extracellular signals into biochemical or electrophysiological responses within a cell. The signalling species is a specific endogenous molecule (e.g., neurotransmitter or hormone) which binds to the receptor. This results in activation of receptor and intracellularly located G proteins and propagation of the signal to effector molecules such as adenylyl cyclase. This enzyme converts ATP into cyclic AMP, the classical "second" messenger.Many neurotransmitters and hormones are chiral compounds. Among them are proteins and peptides, such as FSH (follicle stimulating hormone) and the endorphins, respectively. They are composed of natural amino acids, which, except for glycine, are all chiral. The translation machinery for peptide and protein synthesis has evolved to utilize only one of the chiral forms of amino acids, the L-form. The reason for this is not clear. Amino acids themselves may also act as endogenous signalling molecules for GPCRs. Examples are GABA (r-aminobutyric acid) acting on GABAB receptors, and metabotropic glutamate receptors for which L-glutamate and L-aspartate serve as signalling molecules. Other small endogenous molecules may serve a similar purpose. Among them are the classical biogenic amines, such as (nor)adrenaline, histamine, and serotonin, and numerous other examples, such as leukotrienes, adenosine, and ATP. This group hosts both nonchiral and chiral substances. Dopamine, serotonin, acetylcholine and histamine do not have a chiral center in their structure, whereas others possess one (adrenaline and noradrenaline) or more (adenosine and ATP). w. SOUDIJN et at number of cloned ("orphan") receptors, the endogenous ligand is not known (yet). An important effort to keep track of the latest information on receptors is the G protein-coupled receptor database which is maintained on the Internet (www.gpcr.org!7tm/).The earliest evidence for stereoselective receptor recognition was reported by PIUTII (1886) who pointed out that D-asparagine has a sweet taste, while the natural L-isomer is insipid. Interestingly, PASTEUR (1886) ascribed this finding to the presence of an optically active substance in the nervous mechanism of taste. Given our current understanding of olfactory receptors as a special branch of the large superfamily of G protein-coupled receptors, PASTEUR'S statement was well ahead of its time. CUSHNY (1926) was the first to review and pay particular atte...

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Development of 1,4-benzodiazepine cholecystokinin type B antagonists

Cited by 71 publications

References 10 publications

Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK₂) Receptors by Novel Bivalent Ligands

Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK₂) Receptors by Novel Bivalent Ligands

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Enantioselectivity in Drug-Receptor Interactions

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Development of 1,4-benzodiazepine cholecystokinin type B antagonists

Cited by 71 publications

References 10 publications

Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK2) Receptors by Novel Bivalent Ligands

Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK2) Receptors by Novel Bivalent Ligands

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Enantioselectivity in Drug-Receptor Interactions

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Product

Resources

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Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK₂) Receptors by Novel Bivalent Ligands

Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK₂) Receptors by Novel Bivalent Ligands