ABSTRACT
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.
Subject(s)
Antipsychotic Agents/pharmacology , Schizophrenia/drug therapy , Adolescent , Adult , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/therapeutic use , Child , Corpus Striatum/drug effects , Disease Progression , Dopamine/physiology , Dopamine Agonists/pharmacology , Dopamine Antagonists/adverse effects , Dopamine Antagonists/pharmacokinetics , Dopamine Antagonists/pharmacology , Dopamine Antagonists/therapeutic use , Dopamine D2 Receptor Antagonists , Drug Design , Drug Evaluation, Preclinical , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Agonists/therapeutic use , Female , Genetic Predisposition to Disease , Humans , Limbic System/drug effects , Male , Rats , Receptors, Dopamine D2/physiology , Receptors, Neurotransmitter/drug effects , Receptors, Tachykinin/drug effects , Schizophrenia/genetics , Schizophrenia/metabolism , Serotonin Antagonists/pharmacology , Serotonin Antagonists/therapeutic useABSTRACT
The new generation hypnotic drugs, zolpidem, zopiclone and zaleplon, are at least as efficacious in the clinic as benzodiazepines and may offer advantages in terms of safety. These drugs act through the BZ binding sites associated with GABAA receptors, but show some differences from benzodiazepines in pharmacological effects and mechanisms of action. Of particular interest is the finding that zolpidem shows a wide separation between doses producing sedative effects and those giving rise to other behavioural actions, and induces less tolerance and dependence than benzodiazepines. Zolpidem also demonstrates selectivity for GABAA receptors containing alpha1 subunits. Recent studies using genetically modified mice have confirmed that receptors containing alpha1 subunits play a particularly important role in mediating sedative activity, thus providing an explanation for the pharmacological profile of zolpidem.
