JP‐1302: a new tool to shed light on the roles of <i>α</i><sub>2C</sub>‐adrenoceptors in brain

Tricklebank, Mark D.

doi:10.1038/sj.bjp.0707007

Cited by 8 publications

(7 citation statements)

References 14 publications

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“…The molecular docking experiments of JP-1302, a selective antagonist of the α2c-AR subtype [18, 19], have yielded different binding modes for each α2-ARs binding sites (figure 7), mostly due to AAV8 variation, but also AAV7 and AAV9 variations have played an important role. The glycine residue found at position AAV8 in the α2c-AR subtype, allows the accommodation of the ligand’s acridine ring into a hydrophobic pocket located in the extracellular part of the receptor, between the upper parts of helices 6 and 7.…”

Section: Resultsmentioning

confidence: 99%

“…However, because of the common mechanisms for the signal transduction and the very high degree of sequence homology (more than 80%) exhibited by α2-ARs, information regarding subtype-selective compounds is still limited. At the time of this manuscript preparation, only a few compounds have been reported to be α2-ARs subtype-selective: the agonists guanfacine for α2a-AR and R-(+)-m-nitrobiphenylinde oxalate for α2c-AR and the antagonists BRL-44408 for α2a-AR, JP-1302 and OPC28326 for α2c-AR [13-19]. As an accomplishment of our previous works [20, 21], this paper combines structural bioinformatics approaches like homology modeling and docking to identify the main molecular characteristics which regulate the selectivity within the α2-ARs subtypes.…”

Section: Introductionmentioning

confidence: 99%

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Structural determinants of the alpha2 adrenoceptor subtype selectivity

Halip¹,

Curpăn²,

Mracec³

et al. 2011

Journal of Molecular Graphics and Modelling

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Alpha2-adrenergic receptor (α2-AR) subtypes, acting mainly on the central nervous and cardiovascular systems, represent important targets for drug design, confirmed by the high number of studies published so far. Presently, only few α2-AR subtype selective compounds are known. Using homology modeling and ligand docking, the present study analyzes the similarities and differences between binding sites, and between extracellular loops of the three subtypes of α2-AR. Several α2-AR subtype selective ligands were docked in the active sites of the three α2-AR subtypes, key interactions between ligands and receptors were mapped, and the predicted results were compared to experimental results. Binding site analysis reveals a strong identity between important amino acid residues in each receptor, the very few differences being the key towards modulating selectivity of α2-AR ligands. The observed differences between binding site residues provide an excellent starting point for virtual screening of chemical databases in order to identify potentially selective ligands for α2-ARs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural determinants of the alpha2 adrenoceptor subtype selectivity

Halip¹,

Curpăn²,

Mracec³

et al. 2011

Journal of Molecular Graphics and Modelling

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“…The actions of JP‐1302 left, however, many unanswered questions, not only about the action of the particular compound, but more importantly about the physiological role of α 2C ‐ARs in general . One obvious concern is whether the effects observed with JP‐1302 were only idiosynchratic to its chemical nature.…”

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confidence: 99%

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

Sallinen

Holappa

Koivisto

et al. 2013

Basic Clin Pharma Tox

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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...

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“…However, the lack of selective pharmacological tools has limited research on the ␣ 2 -subtype responsible for effecting nasal vasoconstriction. JP-1302 is a selective ␣ 2c -antagonist that has been recently described in the scientific literature [15,16] . In this study, we sought to determine the potential nasal congestive effects of this compound on the cat, using acoustic rhinometry.…”

Section: Introductionmentioning

confidence: 99%

Alpha-2c-Adrenergic Receptors Contribute to Basal Nasal Patency in the Anesthetized Cat

Mingo¹,

Corboz²,

Salisbury³

et al. 2010

Pharmacology

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Background: Nasal congestion is the most troublesome symptom associated with a variety of upper airway diseases, including allergic rhinitis and the common cold. A better understanding of the mechanisms that regulate nasal cavity caliber may engender the development of novel treatment strategies. It is well accepted that α-adrenergic (both α₁ and α₂) mechanisms play a fundamental role in the control and maintenance of basal nasal patency. JP-1302 is a selective α_2c-subtype antagonist that has been recently described in the scientific literature. Thus, we sought to examine the potential effects of this new pharmacological tool on basal nasal patency. Methods: Using acoustic rhinometry, we studied the activity of the selective α_2c-antagonist JP-1302 on nasal cavity volumes in an anesthetized cat. Cumulative concentrations of JP-1302 were applied directly into the right nasal cavity. Changes in the nasal cavity geometry of the drug-treated naris relative to the untreated left nasal cavity were determined. In separate studies, the nonselective α₂-antagonist yohimbine and the nonselective α₁-antagonist prazosin were run as comparators. Systolic blood pressure was measured at the hind leg, using an ultrasonic Doppler flow detector. Results: JP-1302 (0.03, 0.1, 0.3 and 1.0%) administered by the intranasal route decreased nasal cavity volumes from baseline values by 17, 25, 40 and 40%, respectively. Yohimbine (0.03, 0.1, 0.3 and 1.0%) decreased volumes by 19, 36, 46 and 53%, and topical administration of the nonselective α₁-antagonist prazosin (0.001, 0.003, 0.01, 0.03 and 0.1%) decreased volumes by 6, 47, 56, 64 and 71%, respectively. JP-1302, yohimbine and prazosin, at the dose level tested, did not alter the blood pressure. Conclusions: The present set of experiments indicates that both α₁- and α₂-adrenergic receptors are involved in the maintenance of basal nasal patency in the cat. Moreover, α_2c-receptors may play a significant role in the sympathetic control of upper airway function.

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JP‐1302: a new tool to shed light on the roles of α_2C‐adrenoceptors in brain

Cited by 8 publications

References 14 publications

Structural determinants of the alpha2 adrenoceptor subtype selectivity

Structural determinants of the alpha2 adrenoceptor subtype selectivity

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

Alpha-2c-Adrenergic Receptors Contribute to Basal Nasal Patency in the Anesthetized Cat

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JP‐1302: a new tool to shed light on the roles of α2C‐adrenoceptors in brain

Cited by 8 publications

References 14 publications

Structural determinants of the alpha2 adrenoceptor subtype selectivity

Structural determinants of the alpha2 adrenoceptor subtype selectivity

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

Alpha-2c-Adrenergic Receptors Contribute to Basal Nasal Patency in the Anesthetized Cat

Contact Info

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JP‐1302: a new tool to shed light on the roles of α_2C‐adrenoceptors in brain

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