Vol 8, No 3 - Drug Discovery and Proof of Concept
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I n  t h i s  i s s u e ... Brain biochemistry is rich and complex, and brain func- tions are also varied, complex, and interdependent. Drugs for treating central nervous system (CNS) diseases act on the biochemical machinery of the brain, on cell mem- brane or nucleus receptors, on second messengers, and on neurotransmitters. This leads to changes in macro- scopically measurable brain functions such as perception, motor activity, memory, emotion, consciousness, and many other functions that enable our adaptation to our changing internal, physical, and social environments. The first CNS drug discoveries during the 1950s and 1960s were serendipitous to some extent, but also guid- ed by astute hypotheses. At that time, a series of useful drugs could be developed by one researcher, or by a rather small team, which has become near to impossible now. Several drugs that were discovered in those times remain standards, to be used as comparatives in the cur- rent evaluation of the clinical efficacy of drugs in devel- opment. Researchers in pharmaceutical sciences and industries now have a huge knowledge base in fundamental and clinical neurosciences, from which to develop innovative drug treatments for neurological or psychiatric diseases and disorders. Indeed, nowadays, a pharmacological com- pound is described in an exhaustive manner, covering all its influences (by analogy with an antibiogram): ie, a receptorgram, a transportergram, an enzymogram, a genogram, a proteinogram, a metabogram; these terms concern the list of all biochemical constituents that are changed during drug administration. To this biochemical level of description, one can now add a physiological level, ie, the drugs’ influences on neuronal networks devoted to given CNS functions. Neuroimaging technologies are rel- evant tools at this level of analysis. As an illustration of a physiological description of pharmacodynamics, some antidepressants influence the automatic and noncon- scious perception of others’ emotions, by dampering the activity of the amygdala and related structures. The final goal of neurologic or psychiatric drug treatment is the control of symptoms, acutely, chronically, or with a pre- ventive goal, ie, to act in a bottom-up manner, from mol- ecules to mind. In this issue of Dialogues in Clinical Neuroscience, the authors describe how researchers look for new therapeu- tic compounds, ie, how they explore unknown domains to discover those structure/activity relations that could provide therapeutic effects with minimal side effects. An overall conclusion to be drawn from these articles is that the challenge of new drug discovery is immense, and requires intelligence and the use of shortcuts, as well as a thorough and cautious approach. To these research com- petences, one should also add real administrative talent. A group of lazy men once returned after a terrible day's work: there was work for at least six people, but fortu- nately there were twelve of them! Looking at the contri- butions by the authors of this issue, I am persuaded that the reverse situation prevails in the domain of drug dis- covery: a small number of people have to achieve a lot. A State of the art paper on the expression profiling of drug response, from genes to pathways, by Ralf Herwig and Hans Lehrach, provides a relevant introduction to the theme of drug discovery and proof of concept. Indeed, the domain of therapeutics will benefit from innovative ideas on how to identify targets of medication. The recent functional  genomic  technology  with  DNA  arrays  or microarrays, ie, the capacity to measure the transcription of thousands of genes into RNA molecules, enables us to study the configuration of genomic changes induced by a given drug treatment. This advance offers a realistic approach to pharmacology, in the sense that the phar- macodynamics of drugs is now addressed at its actual level of complexity, taking into account, at least theoreti- cally, all changes in protein synthesis. The authors describe the DNA transcription techniques and then review the dif- ficulties and the pitfalls of these techniques at several lev- els, ie, in the laboratory, in data analysis, in statistics, in standardization, and in the necessary international col- laboration between institutions. The authors then give their view as to how many new drugs could be found on the basis of well-defined molecular targets; they also mention  avenues  for  the  integration  of  functional genomics techniques with other techniques, with the aim of understanding the successive steps from DNA trans- duction to neuronal metabolism, to neuronal networks and then to global physiological systems, analyzed macro- scopically. Functional genomic technology can lead, not only to new medications in neurology and psychiatry, but also to a more efficient prediction of the efficacy and safe- ty of a given medication for a given patient. In his Pharmacological aspects paper, Michael Spedding discusses new directions for drug discovery. First, he