Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes.2. Syntheses and biological activities of 1,4-dialkyl-,1,4-dibenzyl and 1-benzyl-4-alkyl-2-(4',5'-dihydro-1' H-imidazol-2'yl)piperazines and isosteric analogues of imidazoline

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Structure–activity relationships on adrenoceptors and imidazoline-preferring binding sites (I 1,2 -PBSs). Part 1: weak intramolecular H-bond and conformational flexibility in a new I 1 -PBS-selective imidazoline analogue, trans 1-(4′,5′-dihydro-1′ H -imidazol-2′-yl)methyl-2-hydroxyindane (PMS 952)

peer reviewedThe highly selective I1-PBS imidazoline analogue PMS 952 has been selected to study the incidence of intramolecular hydrogen bond and molecular flexibility on its biological activity. On one hand, the weak energy difference between three calculated conformers does not support the stabilization of one conformer by an internal hydrogen bond. The 3-D electrostatic map confirms this feature and the solvent effect does not significantly modify the relative energy of these conformers. On the other hand, the conformational spaces of the neutral and ionized forms present a great number of equilibrium structures, in a short energetic range (20 Kcal). The results are representative of an exceptional conformational flexibility due to a cooperative effect between several parts of the molecule

Effect of S-21663 (PMS 812), an imidazoline derivative, on glucose tolerance and insulin secretion in a rat model of type II diabetes

International audienceWe have studied the activity of S-21663 (PMS 812), a new imidazoline derivative, in a rat model of Type II diabetes obtained by i.v. injection of a low dose (35 mg/kg) of streptozotocin, using glucose tolerance tests. Glucose tolerance and insulin secretion were measured as the delta G and the delta l, i.e., the respective increase in glycemia and insulinemia over 30 min after the glucose load. The rate of glucose disappearance was calculated as the K coefficient and the insulin response to glucose as the delta l/delta G. After i.p. injection of S-21663, delta G (millimoles per liter per minute) was decreased (71.7 +/- 10.1 vs. 112.6 +/- 15.1; P < .05), whereas K was increased (3.3 +/- 0.3 vs. 1.5 +/- 0.1; P < .05). Insulin secretion was also largely improved (delta l/delta G: 90.9 +/- 22.2 vs. 18.3 +/- 2.6; P < .05). Oral administration of the product was almost as efficient as i.p. injection. Chronic treatment (15 days) increased the efficiency. Insulin secretion measured in vitro at both 2.8 and 16.6 mM glucose was quadrupled by S-21663 (100 microM). S-21663 binds neither to alpha-2 adrenoceptors nor to known imidazoline binding sites. S-21663 can be considered as a potential hypoglycemic agent in Type II diabetes