KU14R

A new I(3)-R antagonist, KU14R (2 (2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole), which selectively blocks the insulin secretory response to imidazolines. KU14R partially attenuated responses to Imidazole-4-acetic acid-ribotide (IAA-RP). The effects of KU14R on stimulus secretion-coupling in normal mouse islets and beta cells was compared by measuring KATP channel activity, plasma membrane potential, cytosolic calcium concentration ([Ca2+]c) and dynamic insulin secretion. In the presence of 10 mmol/l but not of 5 mmol/l glucose, KU14R (30, 100 or 300 micromol/l) was ineffective. KATP channel was blocked by KU14R (IC50 31.9 micromol/l, Hill slope -1.5). KU14R does not act as an antagonist of either efaroxan or S22068 at an imidazoline site in vivo.

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.[Pubmed:16283242]

Diabetologia. 2005 Dec;48(12):2567-75.

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 KATP channel activity, plasma membrane potential, cytosolic calcium concentration ([Ca2+]c) and dynamic insulin secretion. RESULTS: In the presence of 10 mmol/l but not of 5 mmol/l glucose, efaroxan (100 micromol/l) strongly enhanced insulin secretion by freshly isolated perifused islets, whereas KU14R (30, 100 or 300 micromol/l) was ineffective at both glucose concentrations. Surprisingly, the insulinotropic effect of efaroxan was not antagonised by KU14R. KATP channels were blocked by efaroxan (IC50 8.8 micromol/l, Hill slope -1.1) and by KU14R (IC50 31.9 micromol/l, Hill slope -1.5). Neither the KATP channel-blocking 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 [Ca2+]c in single beta cells and whole islets at 5 mmol/l glucose. The increase in [Ca2+]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 KATP channels. The imidazole compound is less efficient in raising [Ca2+]c; in particular, it lacks the ability of the imidazoline to potentiate the enhancing effect of energy metabolism on Ca2+-induced insulin secretion.

Effects of the imidazoline ligands efaroxan and KU14R on blood glucose homeostasis in the mouse.[Pubmed:12409010]

Eur J Pharmacol. 2002 Nov 1;454(1):95-102.

The putative imidazoline I(3) receptor antagonist 2-(2-ethyl-2,3-dihydrobenzo[b]furan-2-yl)-1H-imidazole (KU14R) has been shown to block the effects of the atypical I(3) agonist efaroxan at the level of the ATP-sensitive K(+) (K(ATP)) channel in isolated pancreatic islet beta cells, but its effects in vivo are not known. We have therefore investigated the effects of KU14R on blood glucose and insulin level in vivo. When KU14R was administered before or after a hypoglycaemic dose of efaroxan, the fall in blood glucose was at least additive. When the antihyperglycaemic imidazoline ligand S22068 was administered after a dose of KU14R, it did not alter the hypoglycaemic response. In the mouse isolated vas deferens preparation, neither rauwolscine (at concentrations which competitively antagonised the inhibitory response to 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK14304)) nor KU14R affected inhibition produced by S22068. At 10(-4) M, KU14R had weak alpha(2)-adrenoceptor antagonist activity. We conclude that KU14R does not act as an antagonist of either efaroxan or S22068 at an imidazoline site in vivo.

Stimulation of insulin secretion in clonal BRIN-BD11 cells by the imidazoline derivatives KU14r and RX801080.[Pubmed:11058411]

Pharmacol Res. 2000 Dec;42(6):575-9.

The imidazoline derivatives KU14R and RX801080 have each been reported to antagonize imidazoline-stimulated insulin secretion. This study investigated the effects of a range of concentrations of both KU14R and RX801080 on insulin secretion from the clonal pancreatic beta cell line, BRIN-BD11. In the presence of a stimulatory (8.4 m m) glucose concentration, both KU14R (50-200 microm;P< 0.01 to P< 0.001) and RX801080 (50-200 microm;P< 0.01 to P< 0.001) were found to dose-dependently stimulate insulin secretion. The imidazoline efaroxan (200 microm) stimulated insulin secretion (P< 0.001) from BRIN-BD11 cells. This insulinotropic effect was significantly augmented by KU14R (100-200 microm;P< 0.01 to P< 0.001) and RX801080 (200 microm;P< 0.05). Insulin secretion from BRIN-BD11 cells was also stimulated by the novel guanidine derivative BTS 67 582 (200 microm;P< 0.001). This secretagogue action was augmented both by KU14R (25-200 microm;P< 0.001) and by RX801080 (25-200 microm;P< 0.05 to P< 0.001). It is concluded that, rather than acting as antagonists of imidazoline-induced insulin secretion, the imidazoline derivatives KU14R and RX801080 are themselves potent insulinotropic agents.

The effect of the putative endogenous imidazoline receptor ligand, clonidine-displacing substance, on insulin secretion from rat and human islets of Langerhans.[Pubmed:9138700]

Br J Pharmacol. 1997 Mar;120(5):926-32.

1. The effects of a rat brain extract containing clonidine-displacing substance (CDS), a putative endogenous imidazoline receptor ligand, on insulin release from rat and human isolated islets of Langerhans were investigated. 2. CDS was able to potentiate the insulin secretory response of rat islets incubated at 6 mM glucose, in a dose-dependent manner. The magnitude of this effect was similar to that in response to the well-characterized imidazoline secretagogue, efaroxan. 3. CDS, like other imidazoline secretagogues, was also able to reverse the inhibitory action of diazoxide on glucose-induced insulin release, in both rat and human islets. 4. These effects of CDS on secretion were reversed by the imidazoline secretagogue antagonists, RX801080 and the newly defined KU14R, providing the first evidence that imidazoline-mediated actions of CDS can be blocked by specific imidazoline antagonists. 5. The effects of CDS on insulin secretion were unaffected when the method of preparation involved centri-filtration through a 3,000 Da cut-off membrane or when the extract was treated with protease. These results confirm that the active principle is of low molecular weight and is not a peptide. 6. Overall, the data suggest that CDS behaves as a potent endogenous insulin secretagogue acting at the islet imidazoline receptor.

Clotrimazole and efaroxan stimulate insulin secretion by different mechanisms in rat pancreatic islets.[Pubmed:9453462]

Naunyn Schmiedebergs Arch Pharmacol. 1997 Dec;356(6):763-8.

It is now well established that the imidazoline insulin secretagogue efaroxan mediates its effects by inducing closure of ATP-sensitive potassium channels in the pancreatic beta-cell, leading to membrane depolarisation, Ca2+ influx and increased insulin secretion. However, a recent study has shown that efaroxan may also act as a blocker of a second class of potassium channel (the Kmaxi channel) in red blood cells, raising the possibility that its effects in islets could be mediated by interactions with both types of channel. Since the antimycotic imidazole compound clotrimazole is a highly potent blocker of Kmaxi channels, we have studied the effects of this drug on insulin secretion. Clotrimazole stimulated insulin secretion from rat islets of Langerhans incubated in the presence of 6 mM glucose, in a dose-dependent manner. Experiments performed at different glucose concentrations showed that the actions of clotrimazole were most prominent at low glucose concentrations whereas it did not enhance secretion beyond the rate induced by 20 mM glucose. The insulinotropic action of clotrimazole was temperature dependent but was independent of extracellular calcium. Clotrimazole appeared to block ATP-sensitive potassium channels in islets since, like efaroxan and glibencamide, it was able to prevent the inhibitory effects of diazoxide on glucose-induced insulin secretion. However, neither the direct stimulatory effect of clotrimazole on insulin release nor the abilty of clotrimazole to reverse the inhibitory actions of diazoxide was sensitive to blockade by the imidazoline secretagogue antagonist KU14R. Overall, the results suggest that clotrimazole exerts an insulinotropic effect in pancreatic beta-cells that is distinct from the actions of imidazoline secretagogues such as efaroxan. Clotrimazole can increase insulin secretion at sub-maximal glucose concentrations by an action which appears to be independent of membrane ion channel events.