Recent advances in novel atypical antipsychotic agents: potential therapeutic agents for the treatment of schizophrenia

Abstract

There are now numerous drugs in advanced stages of clinical testing as potential antipsychotics. The major focus of development of antipsychotics is serotonin (5-HT)_2A antagonism, based on the hypothesis that this property is a critical facet of the pharmacology of clozapine and risperidone. These drugs have been found to exhibit relatively potent 5-HT_2A antagonism compared to their dopamine D₂ antagonistic effects. A large number of other antipsychotics with a similar 5-HT_2A/D₂ profile have been identified. In general, these compounds have minimal cataleptic effects at doses that block dopamine receptor agonist-induced behaviour, and have highly selective effects on mesolimbic dopamine neurones. Because they differ in relative potency as antagonists of a variety of other key receptors (e.g., D₁, D₂, D₃, D₄, D₅, 5-HT_2A, 5-HT_2C, 5-HT₆, 5-HT₇, M₁ and α₁-adrenoceptors), it is likely that these compounds will have significantly different side effects and efficacy profiles (multi-acting receptor targeted agents [MARTA]). Some may be effective in treating negative symptoms and improving cognitive dysfunction. The potential usefulness of N-methyl-D-aspartate (NMDA) receptor agonists for schizophrenia is limited by possible epileptogenic or neurotoxic side effects. In this respect, ligands at strychnine-insensitive glycine binding sites of the NMDA receptor ion channel complex and metabotropic glutamate receptors (mGluR) are expected to have relatively few side effects. A novel sigma₁ receptor antagonist appears to be of particular interest based upon its ability to block the behavioural effects of phencyclidine (PCP). The close relationship between some neuropeptides, such as cholecystokinin and neurotensin, and dopaminergic systems in the brain is sufficient to sustain interest in these apart from the tantalising possibility of mediation by a neuropeptide system of some of the psychopharmacology of schizophrenia.

• α1-adrenergic agents
• antipsychotic agents
• cholecystokinin receptor antagonists
• dopaminergic agents
• glutamate receptor agonists
• glutamate receptor antagonists
• ionotropic glutamate receptor antagonists
• multi-acting receptor targeted agents
• neurotensin receptor antagonists
• serotoninergic agents
• sigma1 receptor antagonists