Role of α<sub>2</sub>-adrenoceptors in Electrical Field Stimulation–induced Contraction of Pig Nasal Mucosa and Pharmacologic Characterization of a Novel α<sub>2C</sub>-adrenoceptor Agonist

Corboz, Michel R.; Rivelli, Maria A.; Shah, Himanshu; Boyce, Christopher W.; McCormick, Kevin D.; Chapman, Richard W.; Hunter, John C.

doi:10.2500/ajra.2013.27.3842

Cited by 5 publications

(7 citation statements)

References 38 publications

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“…[ N -[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]- N -ethyl- N ′-methylurea] or “Compound A” and a chemically similar “Compound B” were found to be highly selective for the α 2C -AR, albeit with poor brain penetration. These compounds are being investigated for effects on peripheral vasoconstriction ( 245 , 247 ).…”

Section: Future Perspective: What Do We Have and What Do We Need?mentioning

confidence: 99%

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

2017

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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.

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Section: Future Perspective: What Do We Have and What Do We Need?mentioning

confidence: 99%

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

2017

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“…Note that blood samples were collected at 90 and 120 minutes post-treatment. a2 or a1-adrenergic receptor subtypes (Corboz et al, 2011(Corboz et al, , 2013. In humans, a2-receptors are prevalent in the nasal mucosa and are found distributed on both capacitance and resistance nasal blood vessels (Andersson and Bende, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…The in vitro profiles of compound A and compound B have been described previously (Corboz et al, 2011(Corboz et al, , 2013. Notwithstanding, these compounds are adrenoceptor agonists that display significant preference for a2c over Fig.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Evaluation of Selectiveα2c-Adrenergic Agonists in Experimental Animal Models of Nasal Congestion

Jia

Mingo

Hunter

et al. 2014

J Pharmacol Exp Ther

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Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective a2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/ pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of a2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 ml). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike dpseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC 80 ) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that a2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

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“…In this regard, the approach of PK/PD modeling is adopted to investigate the dose-response relationship for some drugs in vivo 7–9. However, for other drugs, a simpler relationship between the concentration and effect is modeled mathematically to conceptualize receptor occupancy and drug response in an idealized in vitro system 10–12…”

Section: Introductionmentioning

confidence: 99%

Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice

Zhang¹,

Pan²,

Zhou³

et al. 2014

DDDT

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BackgroundSchisandrin B (Sch B), a dibenzocyclooctadiene compound, is isolated from schisandrae fructus (SF). This study was conducted to compare the time- and dose-response between Sch B- and SF oil (SFO)-induced changes in hepatic and serum parameters in mice.MethodsInstitute of Cancer Research (ICR) mice were given a single oral dose of Sch B (0.125–2 g/kg) or SFO (0.3–5 g/kg). Serum alanine aminotransferase (ALT) activity, hepatic malondialdehyde, and triglyceride (TG) levels were measured at increasing time intervals within 6–120 hours postdosing.ResultsSerum ALT activity was elevated by 60%, with maximum effect (Emax) =45.77 U/L and affinity (KD) =1.25 g/kg at 48–96 hours following Sch B, but not SFO, treatment. Sch B and SFO treatments increased hepatic malondialdehyde level by 70% (Emax =2.30 nmol/mg protein and KD =0.41 g/kg) and 22% (Emax =1.42 nmol/mg protein and KD =2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%–60% (Emax =11.01, KD =0.68 g/kg) and 8%–32% (Emax =9.88, KD =4.47 g/kg) at 12–120 hours and 24–120 hours after the administration of Sch B and SFO, respectively. Hepatic TG level was increased by 40%–158% and 35%–85%, respectively, at 12–96 hours and 6–48 hours after Sch B and SFO treatment, respectively. The values of Emax and KD for Sch B/SFO-induced increase in hepatic TG were estimated to be 22.94/15.02 μmol/g and 0.78/3.03 g/kg, respectively. Both Sch B and SFO increased serum TG (up to 427% and 123%, respectively), with the values of Emax =5.50/4.60 mmol/L and KD =0.43/2.84 g/kg, respectively.ConclusionThe findings indicated that Sch B/SFO-induced increases in serum/hepatic parameters occurred in a time-dependent manner, with the time of onset being serum TG level < hepatic TG level < hepatic index < serum ALT activity. However, the time of recovery of these parameters to normal values varied as follow: serum TG level < hepatic TG level and liver injury < hepatic index. The Emax and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO.

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Role of α₂-adrenoceptors in Electrical Field Stimulation–induced Contraction of Pig Nasal Mucosa and Pharmacologic Characterization of a Novel α_2C-adrenoceptor Agonist

Cited by 5 publications

References 38 publications

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

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

Pharmacological Evaluation of Selectiveα2c-Adrenergic Agonists in Experimental Animal Models of Nasal Congestion

Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice

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Role of α2-adrenoceptors in Electrical Field Stimulation–induced Contraction of Pig Nasal Mucosa and Pharmacologic Characterization of a Novel α2C-adrenoceptor Agonist

Cited by 5 publications

References 38 publications

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

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

Pharmacological Evaluation of Selectiveα2c-Adrenergic Agonists in Experimental Animal Models of Nasal Congestion

Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice

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Role of α₂-adrenoceptors in Electrical Field Stimulation–induced Contraction of Pig Nasal Mucosa and Pharmacologic Characterization of a Novel α_2C-adrenoceptor Agonist