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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 . [ABSTRACT FROM AUTHOR]

The present experiments compared the peripheral and central pharmacological effects of three α2-adrenoceptor agonists: fadolmidine, clonidine, and dexmedetomidine after single intrathecal bolus injections at analgesic dose level in rats. Effects on mydriasis and cardiovascular functions were studied in anaesthetised rats, the effects on sedation/motor performance, body temperature, and gastrointestinal motility were evaluated in conscious rats, and also the effects on brain biogenic amines were studied. All compounds caused dose-dependent mydriasis, a decrease in blood pressure and heart rate, sedation, hypothermia, and inhibition of gastrointestinal transit, but in contrast to the analgesic effects, dexmedetomidine and clonidine were much more potent than fadolmidine. In accordance with the other systemic effects, dexmedetomidine and clonidine, but not fadolmidine, reduced the turnover of the monoamine neurotransmitters, noradrenaline and serotonin, in brain at the analgesic dose. The difference in the systemic effect profile between fadolmidine and clonidine or dexmedetomidine is most probably explained by differences in their ability to spread from the site of administration at the lumbar level into the periphery and/or the brain and further the concentrations of the compounds in the side of action. These results supports that intrathecally administered fadolmidine could have potential to be used as an analgesic agent with less subraspinal or spinal adverse effects at analgesic doses than dexmedetomidine and clonidine. [ABSTRACT FROM AUTHOR]