AbstractThe α2‐adrenoceptors (ARs) are important modulators of a wide array of physiological responses. As only a few selective compounds for the three α2‐AR subtypes (α2A, α2B and α2C) have been available, the pharmacological profile of a new α2C‐selective AR antagonist ORM‐10921 is reported. Standard in vitro receptor assays and antagonism of α2, and α1‐AR agonist ‐evoked responses in vivo were used to demonstrate the α2C‐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 in vitro α2C‐ AR antagonism for ORM‐10921 varied between 0.078–1.2 nM depending on the applied method. The selectivity ratios compared to α2A‐AR subtype and other relevant receptors were 10‐100 times in vitro. The in vivo experiments supported its potent α2C‐antagonism combined with only a weak α2A‐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 α2C‐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 α2C‐AR is a potential therapeutic target in CNS disorders such as schizophrenia or Alzheimer's disease and suggests the potential of α2C‐antagonism to treat such disorders.