Characterisation of new efaroxan derivatives for use in purification of imidazoline-binding sites

Chan, Shyue An; Pallett, Anna L.; Clews, John; Ramsden, Christopher A.; Chapman, JC; Kane, Cheikhou; Dunne, Mark J.; Morgan, Noel G.

doi:10.1016/s0014-2999(98)00466-x

Cited by 25 publications

(48 citation statements)

References 41 publications

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“…In this context it must be mentioned that about 15% of the current amplitude elicited by our stimulation protocol in these experiments cannot be blocked by high sulfonylurea concentrations and is probably not due to K ATP channel activity [26]. Our IC 50 value for the efaroxan block (9 μmol/l) is in good agreement with an early estimate [27], though in some later investigations the channel-blocking effect of efaroxan appeared to be considerably more potent [18]. The Hill coefficient was very close to unity, suggesting that efaroxan interacts with one site on the K ATP channel.…”

Section: Discussionsupporting

confidence: 84%

“…Originally, KU14R was reported to abolish the insulinotropic effect of efaroxan and other imidazolines at c ► equimolar concentrations on statically incubated rat islets [18]. In the present investigation no antagonism between KU14R and efaroxan could be found.…”

Section: Discussionsupporting

confidence: 46%

“…Previous work suggested that the essential difference between KU14R and efaroxan lies in their ability to inhibit K ATP channel activity [18]. By setting up a concentration dependency in the whole-cell configuration, we found that KU14R, like efaroxan, is able to completely block K ATP channels in normal mouse beta cells.…”

Section: Discussionmentioning

confidence: 62%

“…1), was reported to abolish the enhancement of insulin secretion produced by a number of imidazolines, such as efaroxan, RX 821002 and phentolamine. This antagonism was ascribed to KU14R-induced opening of K ATP channels which had been closed by imidazolines [18]. It was also found that KU14R had an inhibitory effect on K ATP channels in inside-out patches from beta cells, but it was concluded that this effect was too weak to stimulate insulin secretion [18].…”

Section: Introductionmentioning

confidence: 99%

“…This antagonism was ascribed to KU14R-induced opening of K ATP channels which had been closed by imidazolines [18]. It was also found that KU14R had an inhibitory effect on K ATP channels in inside-out patches from beta cells, but it was concluded that this effect was too weak to stimulate insulin secretion [18]. Consequently, this compound was classified as a weak partial agonist that is capable of antagonising the effects of the pure imidazoline agonists at the hypothetical imidazoline receptor (I3 site) of pancreatic beta cells [10,19].…”

Section: Introductionmentioning

confidence: 99%

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Essential role of the imidazoline moiety in the insulinotropic effect but not the KATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R

Bleck¹,

Wienbergen²,

Rustenbeck

2005

Diabetologia

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Essential role of the imidazoline moiety in the insulinotropic effect but not the K ATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R Abstract Aims/hypothesis: Imidazolines are a class of investigational antidiabetic drugs. It is still unclear whether the imidazoline ring is decisive for insulinotropic characteristics. Materials and methods: We studied the imidazoline efaroxan and its imidazole analogue, KU14R, which is currently classified as an imidazoline antagonist. The effects of both on stimulus secretion-coupling in normal mouse islets and beta cells were compared by measuring K ATP channel activity, plasma membrane potential, cytosolic calcium concentration ([Ca 2+ ] c ) and dynamic insulin secretion. Results: In the presence of 10 mmol/l but not of 5 mmol/l glucose, efaroxan (100 μmol/l) strongly enhanced insulin secretion by freshly isolated perifused islets, whereas KU14R (30, 100 or 300 μmol/l) was ineffective at both glucose concentrations. Surprisingly, the insulinotropic effect of efaroxan was not antagonised by KU14R. K ATP channels were blocked by efaroxan (IC 50 8.8 μmol/l, Hill slope −1.1) and by KU14R (IC 50 31.9 μmol/l, Hill slope −1.5). Neither the K ATP channelblocking effect nor the depolarising effect of efaroxan was antagonised by KU14R. Rather, both compounds strongly depolarised the beta cell membrane potential and induced action potential spiking. However, KU14R was clearly less efficient than efaroxan in raising [Ca 2+ ] c in single beta cells and whole islets at 5 mmol/l glucose. The increase in [Ca 2+ ] c induced by 10 mmol/l glucose was affected neither by efaroxan nor by KU14R. Again, KU14R did not antagonise the effects of efaroxan. Conclusions/interpretation:The presence of an imidazole instead of an imidazoline ring leads to virtually complete loss of the insulinotropic effect in spite of a preserved ability to block K ATP channels. The imidazole compound is less efficient in raising [Ca 2+ ] c ; in particular, it lacks the ability of the imidazoline to potentiate the enhancing effect of energy metabolism on Ca 2+ -induced insulin secretion.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Essential role of the imidazoline moiety in the insulinotropic effect but not the KATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R

Bleck¹,

Wienbergen²,

Rustenbeck

2005

Diabetologia

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Preparation of novel 2‐(benzo[b]furan‐2‐yl)‐1H‐imidazolines for photoaffinity labelling and affinity isolation of imidazoline binding

Clews

Ramsden

Morgan

2001

Journal of Heterocyclic Chem

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Preparation of analogues of efaroxan and KU14R as potential imidazoline receptor subtype 3 ligands

Farn¹,

Ramsden²,

Morgan³

2008

Journal of Heterocyclic Chem

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The preparation and characterization of new analogues of the imidazoline insulin secretagogue efaroxan 1 are described. These include 1,2,4-triazole, 1,3,4-oxadiazole, pyrimidine, 1,4,5,6-tetrahydropyrimidine and 1,2-dihydro-1,2,4,5-tetrazine analogues. Bromination of 2,3-dihydro-2-ethylbenzo[b]furan-2-carbonitrile 19 gives the 3,3-dibromo analogue 28, which is readily hydrolysed to the corresponding ketone 29. Reduction of this ketone gives the alcohol 31 as a mixture of diastereoisomers that is converted to the fluoride 32 using diethylaminosulfur trifluoride.

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Characterisation of new efaroxan derivatives for use in purification of imidazoline-binding sites

Cited by 25 publications

References 41 publications

Essential role of the imidazoline moiety in the insulinotropic effect but not the KATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R

Essential role of the imidazoline moiety in the insulinotropic effect but not the KATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R

Preparation of novel 2‐(benzo[b]furan‐2‐yl)‐1H‐imidazolines for photoaffinity labelling and affinity isolation of imidazoline binding

Preparation of analogues of efaroxan and KU14R as potential imidazoline receptor subtype 3 ligands

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