TRP channels as drug targets Su Li, John Westwick, Brian Cox and Chris T. Poll Novartis Respiratory Research Centre, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK Abstract. Ca 2+ channel antagonists acting on electrically-excitable cells have proved to be valuable therapeutic agents. The discovery of such agents and the identi¢cation of their molecular target resulted from the investigation of unexpected actions of known pharmacological agents. Ca 2+ in£ux through receptor-operated channels in electrically non-excitable cells such as leukocytes is also functionally important, but to date the channels involved have not been successfully exploited as drug targets for anti- in£ammatory therapy. Until recently, research in this area has been hindered by the lack of obvious molecular identity, but the emergence of the transient receptor potential (TRP) cation family has yielded promising candidates which may underpin the di¡erent receptor-operated Ca 2+ in£ux pathways present in leukocytes. In addition, receptor- operated Ca 2+ in£ux channels are also expressed in electrically-excitable cells suggesting that receptor-operated Ca 2+ entry pathways are likely to be of wider signi¢cance and emphasizes the breadth of their potential as novel, and as yet, unexplored and unexploited drug targets. 2004 Mammalian TRP channels as molecular targets. Wiley, Chichester (Novartis Foundation Symposium 258) p 204^221 Ca 2+ in£ux through plasma membrane channels in all cell types is of fundamental importance in both physiology and pathophysiology, e.g. contraction of muscle cells, neurotransmitter release from nerve terminals, secretion by epithelial cells and leukocyte activation. Therefore modulation of cell function by targeting these channels represents a potentially e¡ective approach for therapeutic intervention. The two main Ca 2+ in£ux pathways which have been under investigation are those Ca 2+ channels which are voltage-activated and those which are not. Although their function is similar ö they regulate the source of one of the most important cytosolic signalling messengers in the body, Ca 2+ ö the drug discovery path trodden by researchers is distinctly di¡erent. Discovery of L-type voltage-operated Ca 2+ channel blockers Blockers of L-type voltage-gated Ca 2+ channels (L-VOCCs) present in vascular smooth muscle are widely used and very e¡ective drugs for the treatment of 204