In this paper, a group from Roche Pharmaceuticals report on the properties of new trace amine associate receptor -1 (TAAR1) agonists. As previously reported by this group, these new compounds have antipsychotic drug like actions, at least after acute administration, in several models. It is interesting that they report only the effects on locomotor-based assays (inhibition of cocaine and PCP-induced locomotion). Presumably this group also examined the efficacies of these compounds in other models used to predict antipsychotic drug-like actions (e.g. normalization of disrupted pre-pulse inhibition; conditioned avoidance response test; inhibition of amphetamine-induced locomotion; inhibition of apomorphine-induced stereotypy, etc) and it will be interesting to see whether these compounds display a broad spectrum of actions at other models of antipsychotic drug actions.

This is important because, as has been reviewed previously (Conn and Roth, 2008), many potential atypical antipsychotic drugs which ultimately proved to be ineffective in humans did not show robust antipsychotic drug-like actions across a broad palette of behavioral models. It will also be important to see if these compounds, which are agonists and partial agonists, maintain efficacy with long-term administration. The compounds also attenuated antipsychotic drug-induced catalepsy suggesting that they might improve motoric side-effects of typical antipsychotic drugs if prescribed in combination therapy.

The group also reports that the compounds attenuate olanzapine-induced weight gain in rats and suggest that this could indicate the compounds may lack the metabolic liabilities associated with atypical antipsychotic drugs and that they may have procognitive actions. Balanced against these positive qualities are the wake promoting effects of these compounds which could limit their utility in individuals with schizophrenia who frequently suffer from sleep disturbances and whose symptoms are frequently exacerbated by disruption of sleep.

Taken together, these are important findings as they provide continued preclinical support for TAAR1 as a potential target for antipsychotic drug development.

References
Conn PJ, Roth BL.Opportunities and challenges of psychiatric drug discovery: roles for scientists in academic, industry, and government settings. Neuropsychopharmacology. 2008 Aug;33(9):2048-60.

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