Pharmacological Characterisation of a Structurally Novel α_2C ‐Adrenoceptor Antagonist <scp>ORM</scp>‐10921 and its Effects in Neuropsychiatric Models

<jats:title>Abstract</jats:title><jats:p>The α<jats:sub>2</jats:sub>‐adrenoceptors (ARs) are important modulators of a wide array of physiological responses. As only a few selective compounds for the three α<jats:sub>2</jats:sub>‐AR subtypes (α<jats:sub>2A</jats:sub>, α<jats:sub>2B</jats:sub> and α<jats:sub>2C</jats:sub>) have been available, the pharmacological profile of a new α<jats:sub>2C</jats:sub>‐selective AR antagonist ORM‐10921 is reported. Standard <jats:italic>in vitro</jats:italic> receptor assays and antagonism of α<jats:sub>2</jats:sub>, and α<jats:sub>1</jats:sub>‐AR agonist ‐evoked responses <jats:italic>in vivo</jats:italic> were used to demonstrate the α<jats:sub>2C</jats:sub>‐AR selectivity for ORM‐10921 which was tested in established behavioural models related to schizophrenia and cognitive dysfunction with an emphasis on pharmacologically induced hypoglutamatergic state by phencyclidine or MK‐801. The Kb values of <jats:italic>in vitro</jats:italic> α<jats:sub>2C</jats:sub>‐ AR antagonism for ORM‐10921 varied between 0.078–1.2 <jats:styled-content style="fixed-case">nM</jats:styled-content> depending on the applied method. The selectivity ratios compared to α<jats:sub>2A</jats:sub>‐AR subtype and other relevant receptors were 10‐100 times <jats:italic>in vitro</jats:italic>. The <jats:italic>in vivo</jats:italic> experiments supported its potent α<jats:sub>2C</jats:sub>‐antagonism combined with only a weak α<jats:sub>2A</jats:sub>‐antagonism. In the pharmacodynamic microdialysis study, ORM‐10921 was found to increase extracellular dopamine levels in prefrontal cortex in the baseline conditions. In the behavioural tests, ORM‐10921 displayed potent antidepressant and antipsychotic‐like effects in the forced swimming test and prepulse‐inhibition models analogously with the previously reported results with structurally different α<jats:sub>2C</jats:sub>‐selective AR antagonist JP‐1302. Our new results also indicate that ORM‐10921 alleviated the NMDA‐antagonist‐induced impairments in social behaviour and watermaze navigation. This study extends and further validates the concept that α<jats:sub>2C</jats:sub>‐AR is a potential therapeutic target in CNS disorders such as schizophrenia or Alzheimer's disease and suggests the potential of α<jats:sub>2C</jats:sub>‐antagonism to treat such disorders<jats:bold>.</jats:bold></jats:p>