Home >> Current Pharmaceutical Design, Volume 7, Number 14

Imidazoline Binding Sites in the Endocrine Pancreas: Can They Fulfil Their Potential as Targets for the Development of New Insulin Secretagogues?

Authors: Morgan, N.G.; Chan, S.L.F.

Source: Current Pharmaceutical Design, Volume 7, Number 14, 1 September 2001 , pp. 1413-1431(19)

Publisher: Bentham Science Publishers

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Abstract:

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 (KATP ) channel in the beta-cell and has been designated I3 . Electrophysiological and biochemical evidence suggest that the I 3 site may be intrinsic to the ion-conducting pore component, Kir6.2, of the KATP 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 b-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 KATP channel-blocking properties.
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  • Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.

    Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.
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