PERSPECTIVES the use of genetically engineered mice to OPINION provide validated models for drug discovery efforts precarious6. Another fundamental difficulty with Magic shotguns versus magic bullets: developing novel CNS therapeutics is the appreciation that the most widely prescribed selectively non-selective drugs for CNS medications, especially those for mood disorders (for example, lithium, anticonvul- sants and antidepressants7) and schizophrenia8 mood disorders and schizophrenia have complex and ill-defined mechanisms of action. As will be summarized below, the dis- Bryan L. Roth, Douglas J. Sheffler and Wesley K. Kroeze covery that the most clinically effective CNS drugs are pharmacologically complex, with Most common central nervous system disorders and schizophrenia — has become pleiotypic actions (that is, they act as ‘magic disorders — such as depression, bipolar one of the most profitable sectors of the phar- shotguns’), has made the development of disorder and schizophrenia — seem to be maceutical market. CNS drugs account for 11 ‘magic bullets’ (that is, drugs selective for a polygenic in origin, and the most effective of the top 25 drugs on the US market, with single molecular target) less likely. medications have exceedingly complex annual US sales in excess of US $17 billion pharmacologies. Attempts to develop (2002 sales figures). Additionally, it is now Why ‘dirty’ drugs might be better more effective treatments for diseases widely accepted that moderately effective Even though clozapine was discovered nearly such as schizophrenia and depression by treatments exist for most of the common 50 years ago3, it remains the ‘gold standard’ discovering drugs selective for single CNS diseases, including schizophrenia, atypical antipsychotic drug because of the molecular targets (that is, ‘magic bullets’) depression, anxiety disorders, insomnia, absence of debilitating extra-pyramidal side- have, not surprisingly, been largely migraine headaches, chronic pain and seizure effects and demonstrated clinical superiority unsuccessful. Here we propose that disorders. This article will focus on the two in treating schizophrenia9 and in reducing designing selectively non-selective drugs largest sectors of the CNS drug market: suicidality10.However, clozapine is also (that is, ‘magic shotguns’) that interact with atypical antipsychotic drugs for schizophrenia associated with severe and potentially life- several molecular targets will lead to new and related disorders, and antidepressants for threatening side effects, including an increased and more effective medications for a variety depression and anxiety disorders. risk of agranulocytosis, seizures, weight gain of central nervous system disorders. Despite the acknowledged potential of and diabetes, and is therefore typically pre- CNS therapeutic agents, few drugs with truly scribed only for individuals with ‘treatment- Despite their enormous potential to alleviate novel mechanisms of action have been intro- resistant’ schizophrenia. Clozapine has a highly human suffering, before the introduction of duced in the past several decades. Indeed, the complex pharmacological profile, with high fluoxetine (Prozac; Eli Lilly) in the late 1980s most widely prescribed drugs — the serotonin- affinity for a number of serotonin (5-HT2A, central nervous system (CNS) therapeutics selective reuptake inhibitors (SSRIs) and 5-HT2C,5-HT6,5-HT7), dopamine (D4), mus- α were not widely embraced as either highly atypical antipsychotic drugs — represent carinic (M1,M2,M3,M4,M5), adrenergic ( 1- α reliable or profitable. This is despite the fact only marginal advances over the prototypes and 2-subtypes) and other biogenic amine that from the 1960s to the 1970s selected areas zimelidine (discovered in 1971 (REF. 2)) and receptors (REF.8 and references cited therein). of CNS drug discovery yielded profitable clozapine (discovered in 1958 (REF. 3)). FIGURE 1 shows the distribution of some of drugs (for example, Valium, Milltown and Because the aetiology of depression and the receptors targeted by clozapine in relation Haldol). This was due, in part, to the lack of schizophrenia is unknown, choosing the to various molecular targets implicated by suitable animal models, disagreements appropriate molecular target for drug dis- genetic studies of schizophrenia (see REFS 4,5 regarding the biological basis of many dis- covery is especially risky. In terms of aetiology, for details). As can be seen in FIG. 1,many of orders, uncertainty regarding the ultimate it is now widely accepted that the major the genes implicated in the aetiology of schizo- mechanism(s) of action and the clinical mental illnesses are polygenic4,5,with substan- phrenia are found in anatomical loci where ineffectiveness of many CNS medications1. tial environmental and, perhaps, epigenetic they could, directly or indirectly, modulate During the past two decades, CNS drug dis- components. The polygenic and non-genetic glutamatergic and dopaminergic neurotrans- covery — particularly in the areas of mood components of major CNS diseases makes mission in the frontal cortex. Clozapine is NATURE REVIEWS | DRUG DISCOVERY VOLUME 3 | APRIL 2004 | 353 © 2004 Nature Publishing Group PERSPECTIVES Dopaminergic GABAergic Glutamatergic α 1 D1 D1 5-HT2A 5-HT2A D1 α 2 D1 mGluR3 GABA D2 5-HT Glu 2A Glu D 2 CN NMDA Glia D3 5-HT1A Thalmocortical VTA Glu D2 GABA D2 D2 CN CN GABA 5-HT2A Striatum GABA Figure 1 | Neuronal circuits implicated in schizophrenia aetiology and treatment. Shown is a schematic diagram of the wiring of the frontal cortex, emphasizing inputs into cortical glutamatergic pyramidal neurons. Some of the various molecular targets implicated as risk factors for schizophrenia are γ shown, including calcineurin (CN) -subunit, the D1- and D3-dopamine receptors (D1, D3) and metabotrophic glutamate receptor 3 (mGluR3). Other molecular targets not shown include catechol-O-methyltransferase, reelin, dysbindin, regulator of G-protein signalling-4 and neuregulin (see REFS 4,5 and references cited therein). Receptors at which clozapine is an antagonist are depicted in red and those at which clozapine is a partial agonist are shown in green (see REF. α α 8 and references cited therein) and include the following: 5-HT1A- and 5-HT2A-serotonin, D1-, D2- and D3-dopamine, 1- and 2-adrenoceptors. For the purposes of clarity, not all of the various molecular targets implicated as risk factors for schizophrenia or those occupied by clozapine are shown. For the sake of simplicity, many other neuronal and biochemical interactions are omitted. GABA, γ-aminobutyric acid; GLU, glutamate; mGluR3, metabotrophic glutamate receptor 3; NMDA, N-methyl-D-aspartate; VTA, ventral tegmental dopamine neuron. 354 | APRIL 2004 | VOLUME 3 www.nature.com/reviews/drugdisc © 2004 Nature Publishing Group PERSPECTIVES thought to normalize glutamatergic and 5-HT1A 5-HT1B dopaminergic neurotransmission in schizo- 5-HT1D phrenia, thereby ameliorating symptoms, via 5-HT1E Atypicality 5-HT2A 5-HT2A complex interactions with a large number of Weight gain 5-HT2C 5-HT2C 5-HT3 molecular targets (FIGS 1,2).These pleiotypic 5-HT5 actions of clozapine are probably responsible 5-HT6 5-HT7 for its exceptionally beneficial actions in D1 Antipsychotic D 9,10 2 D2 schizophrenia and related disorders . efficacy D3 D4 A graphical representation of the relative D α5 affinity values of clozapine and a number of α2A α2B other atypical antipsychotic drugs (aripipra- Adrenergic α2C zole, ziprasidone, zotepine, quetiapine, olanza- α1A Side effects 1B pine, risperidone) and typical antipsychotic M1-muscarinic M2-muscarinic drugs (haloperidol, chlorpromazine) at a por- Muscarinic M3-muscarinic M4-muscarinic tion of the receptorome (that is, that portion of M5-muscarinic γ-A the proteome comprising receptors) is shown γ-B FIG. 2 BZP in .As can be seen, most of the presently NMDA approved atypical antipsychotic drugs have a PCP SERT complex pharmacology, with appreciable NET DAT affinities for a variety of biogenic amine Weight gain H1 H1 receptors. Given the huge potential market for H2 H3 atypical antipsychotic drugs (~US $10 billion H4 EP-3 annually), great effort has been devoted to EP-4 CB-1 uncovering the receptors responsible for effec- Ca2+ channel tiveness, for atypicality and for side effects. The NAR a2/b2 NAR a2/b4 idea has been that if one could design drugs NAR a3/b2 NAR a3/b4 that targeted the appropriate receptors, one NAR a/b2 NAR a7 could develop atypical antipsychotic drugs β 1 1-AR that are more effective than clozapine and β2-AR 10 I1-imidazoline K 100 have fewer side effects. These efforts will be i mGlu1 1,000 mGlu furthered in the future by the precise delin- 10,000 2 mGlu4 eation of the areas of the brain in which the le e e e e e e e e e l e e o n in n in in in n in in o in in z o p o p p p e z p rid z z drug exerts its beneficial effects, as well as char- ra id te rid a a ix a a e na a ip s o e etia nz z th rid x p e m ra Z p u lo io Lo lo h ro rip ip is la C h hio a p acterization of the intracellular biochemical A Z R Q O T T H lu rp F hlo pathways contributing to both effectiveness C and the development of side effects. Figure 2 | Screening the receptorome reveals multiple molecular targets implicated in antipsychotic drug actions. The affinity (Ki) values for clozapine and a large number of other biologically active compounds at various receptors can be found at the PDSP K Database (see Further Information); ‘S /D ’ drugs: not quite clozapine i 2 2 the database is part of the