Over the past two decades, there has been a remarkable increase in: (1) efforts to identify novel, disease-related targets (albeit many of these are unvalidated); (2) the ability to perturb discrete neuronal circuits and their signaling pathways; and (3) a proficiency in designing highly target-selective NCEs. However, this has not translated into any significant increase in either the quality or quantity of NCEs available for disorders of the CNS.
Two areas of especial note in excellent and comprehensive science not translating to meaningful clinical progress are the neurokinen-1 (NK-1) receptor antagonists for pain and depression17 and the various excitotoxic and ROS blockers that failed in stroke. Unfortunately, progress in the area of neurodegeneration is becoming reminiscent of what happened in these two areas: the inability to reduce fundamental research to practice.
CNS drug discovery has a long history of serendipity.11 For example, the first antidepressant, the MAO-1 iproniazid, was originally developed for the treatment of tuberculosis while the anticonvulsant actions of a variety of NCEs were found to be due to the vehicle in which they were dissolved, valproic acid. The complexity of CNS diseases and the empirical nature of the animal models designed to show efficacy have led to many NCEs entering the clinic for one indication and being found useful in another. A key example in this regard is the antipsychotic clozapine.9'18 Discovered in the prebiotech era of the 1970s based on empirical similarities to the dopamine antagonist haloperidol, clozapine was introduced in the early 1970s as a novel antipsychotic with a superior human efficacy profile, the mechanism for which was unknown. The superior attributes of clozapine were limited by the incidence of sometimes fatal agranulocytosis leading to a search for clozapine-like agents lacking this side effect. Clozapine has multiple receptor activities, including interactions with both the DA and 5HT receptor families and with each new receptor identified, clozapine has been found to have addition nuances in its target interactions both in terms of efficacy (5HT6) and side effects (H4). It has also been suggested that these various targets interactions might be additive or synergistic with one another.18 Despite knowledge of the evolving molecular interactions of clozapine, numerous attempts to identify second-generation NCEs with similar efficacy to clozapine in effectively treating the entire spectrum of symptoms associated with schizophrenia have been unsuccessful and there is still no consensus on its mechanism of action.
The paucity of NCEs in the area of CNS disorders suggests that the current reductionist approach, driven largely by advances in molecular biology including a widespread use of transgenic animals that appear to present more questions than they answer, represents a major disadvantage when attempting to find drugs to restore normal function to a system as complex as the CNS. The lack of progress in the areas of pain and depression underlines the shortcoming of this approach and provides further fuel to concept of whether the search for a 'magic bullet,' an NCE active at a single target, has currency in treating diseases with a poly target, poly genomic causality like many of those in the CNS. It has further been argued16,19,20 that current animal models of psychiatric disorders fail to account for basic aspects of synaptic plasticity that are often stress-related and that if these were more widely used both they and the NCEs tested in them might provide a more realistic assessment of the hurdles in advancing NCEs to clinical trials.
The high level of serendipity in the discovery of CNS drugs11 and the extensive need to use clinical information in refining and redefining preclinical activities indicate that while the molecular basis of human CNS diseases is being conceptually defined at the basic preclinical and clinical levels, a process that may take several more decades, safe and effective NCEs should be rapidly advanced along a translational medicine path21 to gain rapid proof of concept, a return in essence to what happened over the past 60 years when: (1) the antidepressant actions of ipronizazid were observed in tubercular humans, and (2) the phenothiazine chlopromazine, designed to treat surgical shock, became the first antipsychotic.
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