title: Pharmacological characterisation of a structurally novel α2C-adrenoceptor antagonist ORM-10921 and its effects in neuropsychiatric models.
abstract: 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.
authors.affiliation: Orion Corporation, Orion Pharma, Research and Development, Turku, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Sallinen
authors.forename: Johanna
authors.initials: J
authors.lastname: Holappa
authors.forename: Ari
authors.initials: A
authors.lastname: Koivisto
authors.forename: Katja
authors.initials: K
authors.lastname: Kuokkanen
authors.forename: Hugh
authors.initials: H
authors.lastname: Chapman
authors.forename: Jyrki
authors.initials: J
authors.lastname: Lehtimäki
authors.forename: Petteri
authors.initials: P
authors.lastname: Piepponen
authors.forename: Jelena
authors.initials: J
authors.lastname: Mijatovic
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Raimo
authors.initials: R
authors.lastname: Virtanen
authors.forename: Jouni
authors.initials: J
authors.lastname: Sirviö
authors.forename: Antti
authors.initials: A
authors.lastname: Haapalinna
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D054837:Quinolizidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000502:physiology
chemical_list: D000166:Acridines; D058669:Adrenergic alpha-2 Receptor Antagonists; D000928:Antidepressive Agents; D001572:Benzofurans; C518829:JP-1302; D018696:Neuroprotective Agents; C587546:ORM-10921; D010879:Piperazines; D054837:Quinolizidines; D018341:Receptors, Adrenergic, alpha-2; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D004298:Dopamine