Aims/hypothesis Inspired by recent speculation about the potential utility of α 2A -antagonism in the treatment of type 2 diabetes, the study examined the contribution of α 2 -antagonism vs other mechanisms to the antihyperglycaemic activity of the imidazoline (±)-efaroxan. Methods Effects of the racemate and its pure enantiomers on isolated pancreatic islets and beta cells in vitro, as well as on hyperglycaemia in vivo, were investigated in a comparative manner in mice. Results In isolated perifused islets, the two enantiomers of efaroxan were equally potent in counteracting inhibition of insulin release by the ATP-dependent K + (K ATP ) channelopener diazoxide but (+)-efaroxan, the presumptive carrier of α 2 -antagonistic activity, was by far superior in counteracting inhibition of insulin release by the α 2 -agonist UK14,304. In vivo, (+)-efaroxan improved oral glucose tolerance at 100-fold lower doses than (−)-efaroxan and, in parallel with observations made in vitro, was more effective in counteracting UK14,304-induced than diazoxide-induced hyperglycaemia. The antihyperglycaemic activity of much higher doses of (−)-efaroxan was associated with an opposing pattern (i.e. with stronger counteraction of diazoxide-induced than UK14,304-induced hyperglycaemia), which implicates a different mechanism of action. Conclusions/interpretation The antihyperglycaemic potency of (±)-efaroxan in mice is almost entirely due to α 2 -antagonism, but high doses can also lower blood glucose via another mechanism. Our findings call for reappraisal of the possible clinical utility of α 2A -antagonistic compounds in recently identified subpopulations of patients in which a congenitally higher level of α 2A -adrenergic activation contributes to the development and pathophysiology of type 2 diabetes.
Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0±1.2 vs. 10.1±1.1; diabetic mice with 180 mg/kg 55P0110, 23.1±0.9 vs. 11.1±1.4; p<0.001 each). Closer examination argued against retarded glucose resorption from the gut, increased glucose excretion in urine, acute insulin-like or insulin sensitising properties, and direct inhibition of dipeptidyl peptidase-4 as the cause of glucose lowering. Hence, 55P0110 seems to act via a target not exploited by any drug presently approved for the treatment of diabetes mellitus. Whereas the insulinotropic sulfonylurea gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49±0.27; 55P0110, 2.99±0.35; gliclazide, 8.97±0.49; p<0.001 each vs. gliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53±0.41; 55P0110, 3.80±0.46; gliclazide, 3.99±0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of fully synthetic substituted quinazolidines with an attractive pharmacological profile that recommends the structures for further evaluation as candidates for the treatment of diabetes mellitus.
The pharmacology of thiazolidinediones (TZDs) seems to be driven not only by activation of peroxisome proliferator-activated receptor-γ (PPARγ), but also by PPARγ-independent effects on mitochondrial function and cellular fuel handling. This study portrayed such actions of the novel hydrophilic TZD compound BLX-1002 and compared them to those of conventional TZDs. Mitochondrial function and fuel handling were examined in disrupted rat muscle mitochondria, intact rat liver mitochondria, and specimens of rat skeletal muscle. BLX-1002 was superior to most other TZDs as an inhibitor of respiratory complex 1 in disrupted mitochondria, but had less effect than any other TZD on oxygen consumption by intact mitochondria and on fuel metabolism by intact tissue. The latter finding was obviously related to the hydrophilic properties of BLX-1002, because high potentials of individual TZDs to shift muscle fuel metabolism from the aerobic into the anaerobic pathway were associated with high ClogP values indicative of high lipophilicity and low hydrophilicity (e.g., % increase in lactate release induced by 10 μmol/l of respective compound: BLX-1002, ClogP 0.39, +10 ± 8%, not significant; pioglitazone, ClogP 3.53, +68 ± 12%, P < 0.001; troglitazone, ClogP 5.58, +157 ± 14%, P < 0.001). The observed specific properties of BLX-1002 could result from relatively strong direct affinity to an unknown mitochondrial target, but limited access to this target. Results suggest 1) that impairment of mitochondrial function and increased anaerobic fuel metabolism are unlikely to account for PPARγ-independent glucose lowering by BLX-1002, and 2) that higher lipophilicity of an individual TZD is associated with stronger acceleration of anaerobic glycolysis.
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