Antipsychotic drugs discovery

If sedatives, barbiturates, antipsychotic drugs, stimulants, opiates and thyroid medications all outperform inert placebos in the treatment of depression, does this mean that any active drug can function as an antidepressant Apparently not. In September 1998 the pharmaceutical company Merck announced the discovery of a novel antidepressant with a completely different mode of action than other medications for depression. This new drug, which they later marketed under the trade name Emend for the prevention of nausea and vomiting due to chemotherapy, seemed to show considerable promise as an antidepressant in... 

Detailed accounts of the discovery of chlorpromazine as an antipsychotic drug have been given by two authors (Caldwell, 1970 Swazey, 1974) an abridged... 

Tricyclic antidepressants—so called because of the characteristic three-ring nucleus—have been used clinically for four decades (Figure 30-1). They closely resemble the phenothiazines chemically and, to a lesser extent, pharmacologically. Like the latter drugs, they were first thought to be useful as antihistamines with sedative properties and later as antipsychotics. The discovery of their antidepressant properties was a fortuitous clinical observation. Imipramine and amitriptyline are the prototypical drugs of the class as mixed norepinephrine and serotonin uptake inhibitors though they also have several other properties. 

Jones AW (2011) Perspectives in drug discovery 6. Antipsychotics. TIAFT Bull 41 (2) 16—19... 

The discovery of the atypical antipsychotic clozapine opened a new era and set new standards in the drug treatment of schizophrenia. Modifications of the diben-zoazepine structure in clozapine resulted in olanzapine and quetiapine, which are among the most frequently used antipsychotic drugs. From a chemical viewpoint, clozapine, olanzapine and quetiapine can be considered as structural analogues. Although they share some common features in their molecular mechanism of action, the three compounds show significant differences in their clinical efficacy and adverse event profile. 

The discovery that the first antipsychotic drugs in the early 1950s, such as chlorpromazine, work in vitro by blocking dopamine receptors led to the hypothesis that schizophrenia was the result of excessive dopaminergic neurotransmission (54, 55). Supporting this hypothesis, dmgs that enhance dopamine action (e.g., cocaine, amphetamines, and L-DOPA) worsen the symptoms of schizophrenia. However, it is clear that 1) not all patients respond to neuroleptic treatment and 2) not all symptoms are reversed by the medication. 

Unfortunately, potentially fatal agranulocytosis appears in 1-2% of patients treated with clozapine (7). This necessitates frequent blood monitoring, which can be inconvenient and expensive. Furthermore, despite its low potential for causing EPS and TD, clozapine causes other, dose-related side effects that can limit its effectiveness in some patients. The precise pharmacological actions of clozapine responsible for its clinical effectiveness are still being debated. Attempts to duplicate elements cf its complex pharmacological profile have led to the discovery of several new atypical antipsychotic drugs that have been approved in the United States for the treatment of schizophrenia. 

Since the discovery of the role of dopamine (DA) as a neurotransmitter in 1958, and the observations that antipsychotic drugs arepostsynaptic DA-receptor antagonists, interest in a dopaminergic hypothesis for the pathophysiology of schizophrenia has existed. However, these theories may be more appropriately oriented toward the treatment of psychosis with antipsychotics. 

Williams M (2009) Commentary genome-based CNS drug discovery D-amino acid oxidase (DAAO) as a novel target for antipsychotic medications progress and challenges. Biochem Pharmacol 78 1360-1365... 

The discovery that D and receptors are preferentially expressed in limbic areas has led to efforts to identify selective inhibitors for these receptors that might have antipsychotic efficacy and low risk of extrapyramidal effects. Clozapine has modest selectivity for D receptors over other DA receptor types. D receptors, preferentially localized in cortical and limbic brain regions in relatively low abundance, are upregulated after repeated administration of most typical and atypical antipsychotic drugs. These receptors may contribute to clinical antipsychotic actions, but agents that are selective or mixed DyS antagonists have not proved effective in the treat-... 

Carlsson discovered that DA is present in large amounts in the brain, and disappears when a person is given the drug reserpine. Administration of the precursor of DA, L-dihydroxyphenylalanine (L-dopa), brings about the reappearance of DA in the brain. Carlsson said, I would put the discovery of dopamine and its role for normal brain functions as a winner, no doubt about it. A good second place would go to the research into the role of dopamine in mental disorders, such as schizophrenia, followed by the third finding the mode of action of antipsychotic drugs. ... 

Just as in life, five-membered heterocycles are of utmost importance to drug discovery. The most conspicuous of all is probably atorvastatin (Lipitor), an HMG-CoA inhibitor. Another bioactive pyrrole shown below is an antipsychotic agent. 

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