Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia—New Developments and Future Perspective

Abstract

α2A- and α2C-adrenoceptors (ARs) are the primary α2-AR subtypes involved in central nervous system (CNS) function. These receptors are implicated in the pathophysiology of psychiatric illness, particularly those associated with affective, psychotic, and cognitive symptoms. Indeed, non-selective α2-AR blockade is proposed to contribute toward antidepressant (e.g., mirtazapine) and atypical antipsychotic (e.g., clozapine) drug action. Both α2C- and α2A-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA) release, with α2C-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine). While the α2A-AR is widely distributed throughout the CNS, α2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α2C-AR plays a more prominent role during states of low endogenous NA activity, while the α2A-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective α2-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the α2A- and α2C-ARs on behavioral markers of mood and cognition, implying that non-selective α2-AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective α2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α2C-AR. ORM-13070 is a useful positron emission tomography ligand, ORM-10921 has demonstrated antipsychotic, antidepressant, and pro-cognitive actions in animals, while ORM-12741 is in clinical development for the treatment of cognitive dysfunction and neuropsychiatric symptoms in Alzheimer’s disease. This review will emphasize the importance and relevance of the α2C-AR as a neuropsychiatric drug target in major depression, schizophrenia, and associated cognitive deficits. In addition, we will present new prospects and future directions of investigation.

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

“…Hyperexcitation of the neuronal networks is observed in different pathologies (Bondy, ) including hepatic encephalopathy (Dynnik et al, ), ischemic stroke (Song et al, ; Turovsky, Turovskaya, Gaidin, & Zinchenko, ), and epilepsy (El‐Hassar, Esclapez, & Bernard, ). Taking into consideration that activation of different subtypes of adrenergic receptors changes the ion channels activity and intensity of release of neurotransmitters, it can be suggested that the selective agonists of adrenergic receptors may be used for the treatment of neurodegenerative diseases (Gleeson, Ryan, Griffin, Connor, & Harkin, ; Uys, Shahid, & Harvey, ). Agonists of adrenergic receptors demonstrate neuroprotective efficiency under oxygen–glucose deprivation (Maier, Steinberg, Sun, Zhi, & Maze, ; Turovsky et al, ), in Parkinson's disease (Peterson, Ismond, Chapman, & Flood, ), and epilepsy (Halonen et al, ).…”

Structural insight into the mechanism of 4-aminoquinolines selectivity for the alpha2A-adrenoceptor

“…A series of 4-aminoquinolines with different linker lengths (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) shown in Fig.1A were synthesized as described previously [8]. All synthesized compounds were identified by proton nuclear magnetic resonance and mass spectrometry ( Supplementary Information, Fig.…”

“…α 2 -ARs have been gradually recognized as promising antipsychotic therapeutic targets, especially for those associated with affective, psychotic, and cognitive symptoms [2]. α 2A -AR is widely distributed in central nervous system (CNS), accounting for 90% of α 2 -ARs, and is associated with regulation and strengthen of memory, analgesia, sedation, and has an anti-epileptic effect [3]. Thus, the activation of the α 2A -AR can improve the clinic symptoms of CNS degenerative diseases.…”

Application of the PET Ligand 11C-ORM-13070 to Examine Receptor Occupancy by the Selective α2C-Adrenoceptor Antagonist ORM-12741: Translational Validation of Target Engagement in Rat and Human Brain

“…An inhibitory G-protein coupled receptor of the neurotransmitter noradrenaline (NA), the α2C-adrenoceptor (α2C-AR) subtype, has attracted considerable interest as a therapeutic target to treat CNS disorders (1). The α2C-AR may be involved in mediation of the fine-tuning effects of NA on central neurotransmission, particularly during stressful conditions.…”

“…Results obtained with gene-targeted (knock-out) mice indicate that manipulation of α2A-AR and α2C-AR activation yields differential behavioural effects in nonclinical tests that are commonly used for assessing antidepressant, antipsychotic or pro-cognitive properties of drugs (1). This has led to the proposition that selective α2C-AR antagonism might be a 3 promising approach for the treatment of neuropsychiatric symptoms, potentially across a wide range of CNS disorders, with an improved therapeutic profile compared to non-selective α2-AR antagonists (1) .…”