α2-adrenoceptor agonists as nasal decongestants

Corboz, Michel R.; Mutter, Jennifer C.; Rivelli, Maria A.; Mingo, Garfield G.; McLeod, Robbie L.; Varty, LoriAnn M; Jia, Yanlin; Cartwright, Mark E.; Hey, John A.

doi:10.1016/j.pupt.2006.03.012

Cited by 23 publications

(25 citation statements)

References 22 publications

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“…Indeed, nasal decongestion is triggered by an active constriction of the venous sinusoids (Kristiansen et al, 1993), and a decrease in nasal cavity pressure after ␣-adrenoceptor agonist administration reflects shrinkage of nasal capacitance vessels (Berridge and Roach, 1986). Several other studies in different species (Lacroix, 1989;Corboz et al, 2003Corboz et al, , 2007Corboz et al, , 2008Wang and Lung, 2003), including human (Johannssen et al, 1997;Corboz et al, 2005), indicated a predominance of the ␣ 2 -adrenenoceptor mechanism in the regulation of capacitance vessels. In addition, ␣ 2 -adrenoceptor proteins are expressed in human nasal mucosa (Corboz et al, 2005) and levels of ␣ 2 -adrenoceptor protein are higher than ␣ 1 -adrenoceptor protein in nasal mucosa of nonallergic and allergic patients (van Megen et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, we reported previously that the ␣ 2C -adrenoceptor subtype is preferentially found in pig nasal mucosa (Corboz et al, 2003), whereas Stafford-Smith et al (2007) demonstrated by in situ hybridization that the ␣ 2C -adrenoceptor mRNA is the only ␣-adrenoceptor mRNA present in human nasal venous sinusoids and arteriovenous anastomoses. Although these pig models (organ chamber and real-time tissue contractility assays) have limitations with regard to translation of results to human, it is worthy of note that pig and human share several similarities such as the anatomy, morphology, physiology, histology, and biochemistry (Hare, 1975;Pound and Houpt, 1978;Corboz et al, 2007) Fig. 9.…”

Section: Discussionmentioning

confidence: 99%

“…The limits of quantitation were 20 ng/g for brain samples and 5 ng/ml for plasma samples. distribution in terms of location and cellular organization (Corboz et al, 2007). Moreover, the pig ␣ 2 -adrenoceptor subtypes are pharmacologically more related to those of human than to those of rodents (Wikberg-Matsson et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Characterization of a Novel α_2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

Corboz

Rivelli²,

McCormick³

et al. 2011

J Pharmacol Exp Ther

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We define the pharmacological and pharmacokinetic profiles of a novel ␣ 2C -adrenoceptor agonist, compound A [N- [3,4-dihydro-4-(1H-imidazol-4-ylmethyl -ethyl-NЈ-methylurea]. This compound has high affinity (K i ) for the human ␣ 2C -adrenoceptor (K i ϭ 12 nM), and 190-to 260-fold selectivity over the ␣ 2A -and ␣ 2B -adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC 50 ϭ 166 nM) and efficacy (E max ϭ 64%) responses at the ␣ 2C -adrenoceptor, much lower potency and efficacy at the ␣ 2A -adrenoceptor (EC 50 ϭ 1525 nM; E max ϭ 8%) and ␣ 2B -adrenoceptor (EC 50 ϭ 5814 nM; E max ϭ 21%) subtypes, and low or no affinity and functional activity at the ␣ 1A -, ␣ 1B -, and ␣ 1D -adrenoceptor subtypes. In the human saphenous vein postjunctional ␣ 2C -adrenoceptor bioassay, compound A functions as a potent agonist (pD 2 ϭ 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC 50 ϭ 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/ kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating ␣ 2C -adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pharmacological Characterization of a Novel α_2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

Corboz

Rivelli²,

McCormick³

et al. 2011

J Pharmacol Exp Ther

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“…Vascular tone is regulated by α adrenergic receptors (αAR) (Johannssen et al, 1997;Corboz et al, 2007;Corboz et al, 2008). The seromucous and Bowman's glands have mainly cholinergic innervation, but adrenergic and peptidergic innervation exists as well .…”

Section: Introductionmentioning

confidence: 99%

Nasal IgA secretion in a murine model of acute stress. The possible role of catecholamines.

Jarillo-Luna

Rivera-Aguilar²,

Pacheco‐Yépez

et al. 2015

Journal of Neuroimmunology

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“…Consequently, selectively targeting and stimulating a2c receptors may provide a novel approach for the treatment of nasal decongestion (Stafford-Smith et al, 2007;Corboz et al, 2011). As previously described, nonselective a2 agonists can elicit constriction of nasal vessels (Corboz et al, 2007). More importantly, nonselective a2 activation has been demonstrated to have significant impact on functional nasal responses and physiology (i.e., nasal blood flows, nasal cavity pressures, and crosssectional areas) in man and animals (Andersson and Bende, 1984;Berridge and Roach, 1986;McLeod et al, 2001;Wang and Lung, 2003).…”

Section: Introductionmentioning

confidence: 97%

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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α2-adrenoceptor agonists as nasal decongestants

Cited by 23 publications

References 22 publications

Pharmacological Characterization of a Novel α_2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

Pharmacological Characterization of a Novel α_2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

Nasal IgA secretion in a murine model of acute stress. The possible role of catecholamines.

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

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α2-adrenoceptor agonists as nasal decongestants

Cited by 23 publications

References 22 publications

Pharmacological Characterization of a Novel α2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

Pharmacological Characterization of a Novel α2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

Nasal IgA secretion in a murine model of acute stress. The possible role of catecholamines.

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

Contact Info

Product

Resources

About

Pharmacological Characterization of a Novel α_2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

Pharmacological Characterization of a Novel α_2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)