The search for novel antipsychotics: pharmacological and molecular targets.
There can be little doubt that the newer, atypical, antipsychotic drugs provide improved treatment for many patients suffering from schizophrenia. However, the significant gains in tolerability produced by these drugs have not generally been accompanied by major advances in clinical efficacy. In particular, negative and cognitive symptoms, which may represent the core deficit of the disease, remain inadequately treated. There is, therefore, a pressing need for more effective drugs. A number of drug discovery and development programmes are currently underway in parallel with significant research into the basic neurobiology of the disease. All antipsychotic drugs currently used in the clinic are antagonists at dopamine D2 receptors, and dopamine neurotransmission seems likely to remain a major biological target for research. However, novel approaches to modulate dopaminergic neurotransmission selectively in relevant brain regions may be required. In addition, a range of non-dopaminergic targets including glutamate, serotonin, neurokinins and acetylcholine are also of major interest. It is likely, however, that the importance of many of these targets may lie in their relationships to and interactions with dopaminergic mechanisms. Finally, advances in genetics and molecular biology are identifying genes associated with a susceptibility to develop schizophrenia. It remains to be seen whether or not these genes and their associated proteins will provide molecular targets for successful drug discovery.
Sanger
David J
DJ
Sanofi-Synthelabo Research, 31 Avenue Paul Vaillant Couturier, 92220 Bagneux, France. david.sanger@sanofi-synthelabo.com
D000293:Adolescent; D000328:Adult; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D003342:Corpus Striatum / Q000187:drug effects; D018450:Disease Progression; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008032:Limbic System / Q000187:drug effects; D008297:Male; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D018039:Receptors, Tachykinin / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018690:Excitatory Amino Acid Agonists; D017448:Receptors, Dopamine D2; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D012702:Serotonin Antagonists; D004298:Dopamine