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The usual reason for a new edition to a book of this type is that the information in previous editions is dated to the point where new advances in the field are hampered by absence of the new knowledge, or, worse, the dated knowledge is now known to be erroneous and incorrect future work is predicted. To a certain extent, both of those scenarios are now operable in the pharmacology of drug discovery thereby suggesting that another edition of this book may be relevant. Pharmacology attempts to understand the mechanisms of action of therapeutic molecules on systems of complexity not yet fully understood; at best, pharmacologists constantly are in a mode of approximation. Because of this, new technology becomes the means to learn more about cellular activity and with advancing technology comes a constantly changing view of drug mechanisms. Specifically two ideas, namely receptor signaling bias and receptor allosteric function, have led to a revision in the strategy of new drug discovery and have revitalized research into receptors as therapeutic targets. In addition, the idea that biased ligands for pleiotropically coupled receptors can cause cell-type dependence of agonist potency ratios effectively negates the use of this basic pharmacologic tool for these molecules. This edition hopefully discusses techniques to capitalize on this new knowledge and address the single most prevalent cause of failure of new drug entities in clinical trials, namely, failure in efficacy. The fact that a discovery and development program can ‘do everything right’ and still fail to produce a useful therapy suggests that a re-evaluation of what we mean by ‘efficacy’ is warranted. The application of concepts regarding protein allostery and biased signaling may allow better definition of efficacy and thus a better targeting of new therapies.
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