Imidazoline receptors: new targets for antihyperglycaemic drugs.
In both animal models of Type 2 diabetes and in man, it has been evident for many years that certain imidazoline drugs can stimulate insulin secretion and improve glycaemia. This suggests that they may be useful new reagents for use in the management of Type 2 diabetes. However, despite their promise, no imidazoline compound has yet come into clinical use as an effective therapeutic agent in diabetes. This should not be taken as evidence of a flaw in the basic hypothesis, but derives, in part, from continuing ignorance about the molecular characteristics of imidazoline binding proteins, and the precise structure-activity relationships of their ligands. In this review, the mode of action of antihyperglycaemic imidazoline compounds is considered, and the possibility discussed that these agents may interact with a unique subtype of imidazoline binding site associated with ATP-sensitive potassium channels. The functional consequences of this interaction are summarised together with evidence that the binding site may actually lie within the channel complex. Additional data implicating the participation of alpha2-adrenoceptors in some actions of imidazolines are evaluated, and examples of relevant drugs having encouraging therapeutic profiles are highlighted. The possibility that some anti-diabetic imidazoline reagents may exert extra-pancreatic effects is also considered. Overall, the article aims to highlight important developments within the field but also draws attention to those areas where controversy remains.
Morgan
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School of Life Sciences, Keele University, Staffordshire, ST5 5BG, UK. n.g.morgan@keele.ac.uk