2.2  Opioid drugs

Opioids represent some of the oldest drugs discovered and they are still crucial to medicine today, particularly for the treatment of pain. The story of their discovery and development illustrates the traditional approach to medicinal chemistry before the era of genomics, proteomics, molecular modelling and in silico drug design. Traditionally, drug research required the discovery of an active compound (morphine in the case of the opioids), either from the natural world or from synthetic compounds produced in laboratories around the world. This compound would then serve as the ‘lead compound’ for further research. Synthetic chemists would make as many different analogues of the lead compound as possible with the aim of finding a compound which had good activity, a minimum of side-effects and favourable pharmacokinetic properties. In the early days, there were no drug design strategies that could be used to guide the medicinal chemist in these efforts and so structures were usually ‘churned out’ in a trial-and-error process. Nevertheless, the results from all this hard graft gradually led to a growing recognition of the various drug design strategies that are used today. The discovery that the opioids act on receptors within the body came relatively late in opioid research (the 1970s), followed by the isolation of endogenous opioids such as the enkephalins, endorphins and dynorphins. Contrast that with the approach favoured by the pharmaceutical industry today, where the initial goal is to identify a molecular target that may play a role in a disease state and then find a lead compound that will interact with that target. Ideally, the target structure is then crystallised along with the bound lead compound. X-ray crystallography is used to determine the crystal structure which can be studied using molecular modelling software to determine how the lead compound binds to the target site. Such studies can be used to guide the medicinal chemist to the analogues which are most likely to have improved binding interactions, activity and selectivity, thus cutting down the synthetic work from many thousands of analogues to a handful. Having said all that, the opioid story is still an important one. It would be wrong to assume that all drug design follows the ‘ideal route’. The molecular targets for lead compounds discovered today are not always known, and even if they are, it is not always possible to crystallise them to produce the crystal structures that would allow molecular modelling studies to be carried out. Therefore, the traditional approaches illustrated in opioid research are still of relevance today.

Finally, the opioid story may be an old one but it is far from over. Current research is leading to a better understanding of the opioid receptors and their binding sites. It may well be that the modern approach will eventually succeed where the traditional approaches have failed, namely in the design of an orally active analgesic that is as effective as morphine in relieving pain, but without the risks of addiction and unacceptable side-effects.