2‐Naphthalenesulphonyl <scp>l</scp>‐aspartyl‐(2‐phenethyl)amide (2‐NAP)‐a selective cholecystokinin CCK<sub>A</sub>‐receptor antagonist

Hull, Robert; Shankley, Nigel P.; Harper, E A; Gerskowitch, V.P.; Black, J.W.

doi:10.1111/j.1476-5381.1993.tb12870.x

Cited by 40 publications

(36 citation statements)

References 33 publications

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“…The final pellet was resuspended in a gassed incubation buffer (Buffer C) in a Teflon-in-glass homogenizer to give a final tissue concentration of 4 mg ml-' (original wet weight). Buffer C also contained 1.25 uM each of phosphoramidon, captopril and bestatin, 12.5 ,uM aprotinin, 1.25 mM dithiothreitol, 0.25 JpM Fe (III) nitrate, 5 yM 2-NAP (pKB at CCKA receptors = 6.5; Hull et al, 1993), 2% BME [50 x] amino acids and 1% MEM [100x] vitamins. These concentrations were reduced by 20% by dilution with the Buffer B in the final incubates.…”

Section: Methodsmentioning

confidence: 99%

Analysis of variation in L‐365,260 competition curves in radioligand binding assays

Harper¹,

Roberts²,

Shankley³

et al. 1996

British J Pharmacology

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Section: Methodsmentioning

confidence: 99%

Analysis of variation in L‐365,260 competition curves in radioligand binding assays

Harper¹,

Roberts²,

Shankley³

et al. 1996

British J Pharmacology

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“…Despite these variations in structure, there is evidence from site-directed mutagenesis that the CCK [30][31][32][33] tetramer and a variety of nonpeptides, including benzodiazepines, quinazolines, and peptoids, all interact with a common residue (Asn353) on the human CCK 2 receptor. 13,14 Taken together, this represents good evidence that the CCK 2 receptor can accommodate a diverse set of structures in the same binding site as the hormone agonist.…”

Section: Introductionmentioning

confidence: 99%

Rationalizing the Activities of Diverse Cholecystokinin 2 Receptor Antagonists Using Molecular Field Points

Low

Vinter

2008

J. Med. Chem.

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Cholecystokinin 2 receptor antagonists encompass a wide range of structures. This makes them unsuitable candidates for existing 3D-QSAR methods and has led us to develop an alternative approach to account for their observed biological activities. A diverse set of 21 antagonists was subjected to a novel molecular field-based similarity analysis. The hypothesis is that compounds with similar field patterns will bind at the same target site regardless of their underlying structure. This initial report demonstrates a linear correlation between ligand similarity and biological activity for this challenging data set. A model generated with three molecules was used to predict the activity of 18 test compounds, with different chemotypes, with a root-mean-square error of 0.68 pKB units. The ability to automatically derive a molecular alignment without knowledge of the protein structure represents an improvement over existing pharmacophore methods and makes the method particularly suitable for scaffold-hopping.

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“…In the present study we employed an argument used previously in our pig studies (Ebenezer & Parrott, 1993), that is, if a specific CCKA antagonist that cannot cross the blood brain barrier does not increase food intake in rats, then it is unlikely that endogenous CCK released from the small intestine during a meal acts as a satiety factor in this species. The aim of the present study was to investigate the effects of systemic administration of the novel CCKA receptor antagonist, 2-NAP [2-naphthalenesulphanyl-L-aspartyl-2-(phenethyl) amide] (Hull et al, 1993), which is unlikely to cross the blood brain barrier (Hull et al, 1993;Baldwin et al, 1994), on food intake in rats given an oral pre-load. We also investigated the ability of 2-NAP to antagonize the inhibitory effects of intraperitoneally administered CCK on food intake in pigs.…”

Section: Introductionmentioning

confidence: 99%

2‐Naphthalenesulphanyl‐L‐aspartyl‐2‐(phenethyl) amide (2‐NAP) and food intake in rats: evidence that endogenous peripheral CCK does not play a major role as a satiety factor

Ebenezer

Baldwin

1995

British J Pharmacology

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1The demonstration that systemic administration of the CCKA receptor antagonist, devazepide, increases food intake in rats has provided the strongest support for the hypothesis that endogenous peripherally released cholecystokinin (CCK) acts as a satiety factor. However, interpretation of these results has been confounded by the fact that devazepide can enter the brain from the systemic circulation and may increase food intake by a central action. The present study was therefore undertaken to confirm the hypothesis that endogenous peripheral CCK is a satiety factor by investigating the effects of a novel CCKA receptor antagonist, 2-NAP, which is unlikely to cross the blood brain barrier, on food intake in rats.2 2-NAP (1-16 mg kg-', i.p.) had no significant effects on the intake of a test meal in rats.3 Pretreatment of rats with 2-NAP (2 mg kg-1, s.c.) abolished the inhibitory effects of exogenous peripheral CCK (5 ,ug kg-', i.p.) on food intake.4 In agreement with previous results, devazepide (50-200 ,ug kg-', i.p.) significantly increased the intake of a test meal in rats. 0 5 The observations that 2-NAP, which is unlikely to penetrate the blood brain barrier, had no effect on food intake, but that 2-NAP abolished the suppressant effect of exogenous peripheral CCK, suggest that endogenously released peripheral CCK is not important as a satiety factor in rats.

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2‐Naphthalenesulphonyl l‐aspartyl‐(2‐phenethyl)amide (2‐NAP)‐a selective cholecystokinin CCK_A‐receptor antagonist

Cited by 40 publications

References 33 publications

Analysis of variation in L‐365,260 competition curves in radioligand binding assays

Analysis of variation in L‐365,260 competition curves in radioligand binding assays

Rationalizing the Activities of Diverse Cholecystokinin 2 Receptor Antagonists Using Molecular Field Points

2‐Naphthalenesulphanyl‐L‐aspartyl‐2‐(phenethyl) amide (2‐NAP) and food intake in rats: evidence that endogenous peripheral CCK does not play a major role as a satiety factor

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2‐Naphthalenesulphonyl l‐aspartyl‐(2‐phenethyl)amide (2‐NAP)‐a selective cholecystokinin CCKA‐receptor antagonist

Cited by 40 publications

References 33 publications

Analysis of variation in L‐365,260 competition curves in radioligand binding assays

Analysis of variation in L‐365,260 competition curves in radioligand binding assays

Rationalizing the Activities of Diverse Cholecystokinin 2 Receptor Antagonists Using Molecular Field Points

2‐Naphthalenesulphanyl‐L‐aspartyl‐2‐(phenethyl) amide (2‐NAP) and food intake in rats: evidence that endogenous peripheral CCK does not play a major role as a satiety factor

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2‐Naphthalenesulphonyl l‐aspartyl‐(2‐phenethyl)amide (2‐NAP)‐a selective cholecystokinin CCK_A‐receptor antagonist