Natural products as probes for new drug target identification

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One traditional aspect of natural products in medical research has been their use in the identification and investigation of the physiological/pathological role of receptors and enzymes as possible targets for drug design programmes. Classical examples of this function of natural products in drug research can be seen in the investigation of the cholinergic system. For example, the importance of alkaloids such as nicotine, physostigmine and curare for research into the nicotinic receptor and muscarine, pilocarpine and the tropane alkaloids on the muscarinic receptor. On binding of a ligand to its cell surface membrane receptor and prior to a physiological/pharmacological response two mechanisms are currently known to be involved in membrane signal transductance. In the minority of cases signal transductance involves the direct opening of an ion channel, for example sodium ion influx, but in the majority of cases involves stimulation of a family of G-proteins and subsequent activation of second messenger systems. For example, the cyclic-AMP/adenylate cyclase system and the phosphoinositol cycle. In this communication, the part played currently by the tumour-promoting and pro-inflammatory phorbol esters from the plant family Euphorbiaceae in furthering our understanding of the role of a group of related kinases from one arm of the phosphoinositol cycle as a signal transduction pathway will be illustrated. The possibilities of using these new receptors as targets for future drug development will also be described.