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

Abstract

Abstract:The a 2 -adrenoceptors (ARs) are important modulators of a wide array of physiological responses. As only a few selective compounds for the three a 2 -AR subtypes (a 2A , a 2B and a 2C ) have been available, the pharmacological profile of a new a 2C -selective AR antagonist ORM-10921 is reported. Standard in vitro receptor assays and antagonism of a 2 , and a 1 -AR agonist -evoked responses in vivo were used to demonstrate the a 2C -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 a 2C -AR antagonism for ORM-10921 varied between 0.078-1.2 nM depending on the applied method. The selectivity ratios compared to a 2A -AR subtype and other relevant receptors were 10-100 times in vitro. The in vivo experiments supported its potent a 2C -antagonism combined with only a weak a 2A -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 a 2C -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 a 2C -AR is a potential therapeutic target in CNS disorders such as schizophrenia or Alzheimer's disease and suggests the potential of a 2C -antagonism to treat such disorders. a 2 -Adrenoceptors (a 2 -ARs) consist of three distinct a 2 -adrenergic receptor subtypes in mammals: a 2A , a 2B and a 2C . They are distributed widely, yet not homogenously, regulating a diverse range of physiological processes including sedation/ vigilance, anxiety, pain/analgesia and cardiovascular function [1][2][3]. In the CNS, the a 2C -ARs are expressed most extensively in the striatum and hippocampus [4][5][6][7]. Valuable information on the discrete functions of each a 2 -AR subtype has been gained by using gene-targeted mice [8,9], but the limited availability of suitable subtype selective ligands has hindered their pharmacological exploration [10].The discovery and pre-clinical profile of a chemically novel and exceptionally selective antagonist at the a 2C -AR, JP-1302, has been described [11]. Compared to other available a 2 -ARs, this agent displays striking (>100 times) selectivity. In the behavioural profiling, JP-1302 showed potent antidepressantand antipsychotic-like properties in the forced swimming test and prepulse inhibition (PPI) paradigms [9,12]. Although part of these results are consistent with those obtained with a 2 -AR knockout mice [9], the antipsychotic-like effect, that is, the reversal of impairme...

Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

“…Its target optimization included D 2 partial agonism with low intrinsic activity, 5-HT 1A partial agonism, and antagonism at 5-HT 2A , a 1B -and a 2C -adrenergic receptors (Maeda et al, 2014), supporting a favorable antipsychotic profile with low EPS risk and potential to treat core symptoms in schizophrenia, including cognitive deficits (Arnt and Skarsfeldt, 1998;Drouin et al, 2002;Marcus et al, 2010;Newman-Tancredi and Kleven, 2011;Sallinen et al, 2013).…”

“…First, it has been shown that the nonselective a 2 -adrenoceptor antagonist atipamezole (Blaxall et al, 1991) improves ID-ED-shift performance in naive rats (Lapiz and Morilak, 2006). Furthermore, the selective a 2C -antagonist ORM-10921 [(1S,12bS)-1-(methoxymethyl)-1-methyl-2,3,4,6,7,12b-hexahydro-1H-benzofuro[2,3-a]quinolizine] reverses cognitive deficits induced by acute treatment with MK-801 [dizocilpine, (5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine] (Sallinen et al, 2013).…”

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

“…All a 1 -adrenoceptor subtypes are coexpressed with 5-HT 2A receptors in frontal cortex, but their relative functional importance is unknown (Santana et al, 2013). Similarly, the a 2C -adrenoceptor field is immature, but antagonism has been proposed to contribute to antidepressant-like and procognitive activity (Quaglia et al, 2011;Sallinen et al, 2013). Clearly, more studies are necessary to explore the role of a-adrenoceptor antagonism for the profile of brexpiprazole.…”

“…Accordingly, an optimized target profile may lead to improvements in both clinical efficacy and adverse effect profile in the treatment of schizophrenia. Furthermore, a broader pharmacological profile (e.g., on selected 5-HT receptors and a-adrenoceptor subtypes) could potentially provide opportunities for the treatment of a variety of other central nervous system (CNS) disorders and symptoms, such as depression and anxiety, as well as stress and impulse control disorders (Drouin et al, 2002;Roth et al, 2004;Arnt et al, 2008;Wong et al, 2008;Sallinen et al, 2013).…”

Validation of [11C]ORM‐13070 as a PET tracer for alpha2c‐adrenoceptors in the human brain

“…Until now, there has been no selective PET tracer available for α 2C ‐ARs to be used in studies aiming to determine whether a novel α 2C ‐AR‐targeted drug candidate can gain access into the CNS and what doses and dosing intervals should be used in clinical trials. α 2C ‐ARs are potential targets in neuropsychiatric and neurodegenerative disorders, as they have been found to modulate the performance of experimental animals in tests predicting efficacy in depression and cognitive dysfunction (Sallinen et al, ; Scheinin et al, ). Several efficacious antipsychotics, most notably clozapine, have significant affinity for α 2C ‐ARs (Kalkman and Loetscher, ).…”