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Potential for antipsychotic and psychotomimetic effects of A_2A receptor modulation

From Vernalis Research Ltd., Wokingham, UK.

Address correspondence and reprint requests to Dr. Scott M. Weiss, Vernalis Research, Oakdene Court, 613 Reading Road, Wokingham, RG41 5UA, UK; e-mail: s.weiss{at}vernalis.com

The discovery of antagonistic interactions between A_2A adenosine receptors and D₂ dopamine receptors in the ventral striatum suggested that A_2A receptor activation might modulate the antipsychotic effects of dopamine receptor antagonists and could provide an opportunity for the development of A_2A receptor agonists as novel antipsychotic drugs. However, there is limited evidence from preclinical and clinical studies that A_2A receptor agonists can exert antipsychotic effects. Furthermore, it remains unclear whether A_2A receptor agonists possess a sufficient safety margin or whether their potent hypotensive effects or extrapyramidal side effects would limit their therapeutic utility as antipsychotic agents. The interaction between A_2A receptors and D₂ receptors also raises the possibility that A_2A receptor antagonists, which hold considerable promise as antiparkinsonian agents, may have dose-limiting psychotomimetic side effects. Preclinical studies using selective A_2A receptor antagonists suggest that this class of compound has a low propensity to elicit psychotomimetic side effects or exacerbate those induced by D₂ receptor agonists.

Dr. Dourish reported equity or ownership in Vernalis in excess of $10,000/year.