Pharmacological Characterisation of a Structurally Novel α2C ‐Adrenoceptor Antagonist ORM‐10921 and its Effects in Neuropsychiatric Models

The 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.