Antagonists schizophrenia

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

Abi-Saab WM, D Souza DC, Moghaddam B et al (1998) The NMDA antagonist model for schizophrenia promise and pitfalls. Pharmacopsychiatry (Suppl)31 104—109... 

If effective neuroleptics are DA antagonists, is there any evidence for increased DA function in schizophrenia ... 

Its activity at Di receptors has been put forward as a possibility and although it has a relatively higher affinity for Di than Dj receptors, compared with typical neuroleptics, it is still a weak antagonist at both and in the absence of evidence for Di (or D5) receptor involvement in schizophrenia the significance of any Di antagonism is unclear. 

Some neuroleptics, including clozapine, are potent 5-HT-receptor antagonists and the possible role of 5-HT in the action of neuroleptics and the development of schizophrenia has recently generated much interest (Busatto and Kerwin 1997). This has centred primarily on 5-HT2A receptors found in the limbic cortex, which are linked to neuronal excitation and believed to mediate the hallucinogenic effects of drugs such as lysergic acid diethylamide (LSD). 

Bristow, LJ, Kramer, MS, Kulagowski, J, Patel, S, Ragan, Cl and Seabrook, GR (1997) Schizophrenia and L745,870, a novel dopamine D4 receptor antagonist. Trends Pharmacol. Sci. 18 186-188. 

Histamine produces its pharmacological actions by three subtypes of receptors the postsynaptic Hi and H2 receptors and the presynaptic H3 receptor. The H3 receptor is mainly located in the central nervous system (CNS), where it acts as an inhibitory autoreceptor in the central histaminergic neuronal pathways [176]. A number of therapeutic applications have been proposed for selective H3 receptor antagonists, including several CNS disorders such as Alzheimer s disease. Attention Deficit Hyperactivity Disorder, Schizophrenia, or for enhancing memory or obesity control. 

An azetidine motif was also present in two series of CBi antagonist compounds disclosed by Vernalis Research [335, 336]. In the former, compound (560) was claimed to have an affinity of 285 nM in transfected HEK293 cells using tritium-labelled (382). Among the preferred indications were psychosis, schizophrenia, smoking cessation and eating disorders associated with excessive food intake. Compound (561) was claimed to have an affinity of 0.8 nM in the same binding assay [336]. 

Rimonabant (382) was also included in a clinical study to assess the safety and efficacy of four novel compounds for the treatment of schizophrenia and psychoaffective disorder [378]. The other compounds included in the trial were a neurokinin NK3 antagonist, a serotonin 2A/2C antagonist and a neurotensin NTSl antagonist. Halopeiidol and placebo groups were used as controls in the study. Sixty-nine patients received (382) (20 mg once per day), which failed to demonstrate efficacy in this trial. The reasons for the lack of efficacy may be due to inadequate dosing or an indication that CBi antagonism is not appropriate in the treatment of this condition. 

Aripiprazole was formulated in the early 1980s to function as a potential dopamine modulator, with both antagonist and agonist activity at the D2 receptor. It is the first D2 partial agonist available for the treatment of schizophrenia and is sometimes referred to as a third-generation antipsychotic. This novel mechanism is... 

---