Imidazoline binding sites in the endocrine pancreas: can they fulfil their potential as targets for the development of new insulin secretagogues?

Curr Pharm Des. 2001 Sep;7(14):1413-31. doi: 10.2174/1381612013397366.


A variety of compounds containing an imidazoline ring have the ability to stimulate insulin secretion. Many of these also improve glycaemia in experimental models of type 2 diabetes and in man, suggesting that this class may be useful in the development of new orally active anti-diabetic drugs. However, the mechanisms by which imidazolines promote insulin secretion have not been clarified. The response does not appear to be due to the binding of ligands to either of the two major types of "imidazoline receptor" defined by pharmacological criteria (I1 and I2 sites) but may result from interaction with a novel imidazoline binding site. One such site has been identified in association with the ATP-sensitive potassium (K(ATP)) channel in the beta-cell and has been designated "I3". Electrophysiological and biochemical evidence suggest that the I3 site may be intrinsic to the ion-conducting pore component, Kir6.2, of the K(ATP) channel, but the effects of imidazoline ligands on insulin secretion can be dissociated from the regulation of Kir6.2. Indeed, there is increasing evidence that some imidazolines can control exocytosis directly, both in beta-cells and in pancreatic alpha-cells. Thus, it is proposed that a further imidazoline binding site is primarily responsible for control of hormone secretion. Evidence is reviewed which suggests that this site occupies a central position within an amplification pathway that also mediates the effects of cAMP in the beta-cell. Characterisation of this site should provide the stimulus for the design of new insulin secretagogues that are devoid of K(ATP) channel-blocking properties.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Binding Sites / physiology
  • Drug Delivery Systems / methods
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / metabolism*
  • Imidazoles / pharmacology
  • Imidazoline Receptors
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Potassium Channels / metabolism
  • Protein Binding / physiology
  • Receptors, Drug / metabolism


  • Imidazoles
  • Imidazoline Receptors
  • Insulin
  • Potassium Channels
  • Receptors, Drug