Intranasal Application of the α 2 -Adrenoceptor Agonist BHT-920 Produces Decongestion in the Cat

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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.

Section: Discussionmentioning

confidence: 99%

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

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“…They also have considerable activity in blood vessels of the nasal mucosa, where their activity can predominate over ␣ 1 -adrenoceptors (Andersson and Bende, 1984;Lacroix and Lundberg, 1989;Wang and Lung, 2003). Indeed, activation of ␣ 2 -adrenoceptors may be the preferred choice for causing nasal vasoconstriction and nasal decongestion (McLeod et al, 2001). The present experiments were therefore performed to evaluate the activity of phenylpropanolamine at vascular ␣ 1 -and ␣ 2 -adrenoceptors.…”

mentioning

confidence: 99%

Phenylpropanolamine Constricts Mouse and Human Blood Vessels by Preferentially Activating α2-Adrenoceptors

Flavahan¹

2004

Phenylpropanolamine (dl-norephedrine) was one of the most widely used therapeutic agents to act on the sympathetic nervous system. Because of concerns regarding incidents of stroke, its use as a nasal decongestant was discontinued. Although considered an ␣ 1 -adrenergic agonist, the vascular adrenergic pharmacology of phenylpropanolamine was not fully characterized. Unlike most other circulations, the vasculature of the nasal mucosa is highly enriched with constrictor ␣ 2 -adrenoceptors. Therefore, experiments were performed to determine whether phenylpropanolamine activates vascular ␣ 2 -adrenoceptors. Mouse tail and mesenteric small arteries and human small dermal veins were isolated and analyzed in a perfusion myograph. The selective ␣ 1 -adrenergic agonist phenylephrine caused constriction of tail and mesenteric arteries and human veins. The selective ␣ 2 -adrenergic agonist UK14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine] caused constriction in tail arteries and in human veins, but not mesenteric arteries. The lack of constriction to UK14,304 was also observed in endothelium-denuded mesenteric arteries. Phenylpropanolamine constricted both types of artery but was 62-fold more potent in tail arteries. In mesenteric arteries, constriction to phenylpropanolamine was not affected by the selective ␣ 2 -adrenergic antagonist, rauwolscine (10 Ϫ7 M) but was abolished by the selective ␣ 1 -adrenergic antagonist, prazosin (3 ϫ 10 Ϫ7 M). In contrast, constriction to phenylpropanolamine in tail arteries and in human veins was inhibited by rauwolscine but not prazosin. Therefore, phenylpropanolamine is a preferential ␣ 2 -adrenergic agonist. At low concentrations, it constricts blood vessels that express functional ␣ 2 -adrenoceptors, whereas at much higher concentrations, phenylpropanolamine also activates vascular ␣ 1 -adrenoceptors. This action likely contributed to phenylpropanolamine's therapeutic activity, namely constriction of the nasal vasculature.Phenylpropanolamine (dl-norephedrine) was one of the most widely used therapeutic agents to act by modulating the sympathetic nervous system. First synthesized in 1912, phenylpropanolamine was introduced as a nasal decongestant in the 1930s (Lasanga, 1988). Its therapeutic use, therefore, predated major discoveries in sympathetic neurophysiology, including the identification of the neurotransmitter norepinephrine (von Euler, 1946, cited in Lasanga, 1988, and the concept of adrenoceptors (Ahlquist, 1948, cited in Lasanga, 1988. Because of concerns regarding episodes of stroke in individuals ingesting phenylpropanolamine, it was withdrawn as a therapeutic agent in 2000 (Kernan et al., 2000).An early report suggested that phenylpropanolamine may possess a cardiac-specific, indirect activity to release norepinephrine from sympathetic nerves (Trendelenburg et al., 1962). However, subsequent studies demonstrated that the cardiovascular effects of phenylpropanolamine result from direct activation of adrenoceptors (e.g., Moya-Huff and Maher, 1987...

“…However, these receptors are distinct from the rat I 2 -receptor to which SCH 79687 binds. We have previously demonstrated that activation of ␣ 2 -adrenergic receptors with drugs such as BHT-920 produced nasal decongestion in the cat (McLeod et al, 2001b). However, the observation that SCH 79687 did not alter the inhibitory actions of clonidine on EFS-induced HSV contractions or affect baseline HSV tone suggest that ␣ 2-adrenoceptors are not activated in vitro at the concentration presently studied.…”

Section: Discussionmentioning

confidence: 49%

“…Peripheral H 3 receptors may serve as a target for the development of novel antiallergy drugs, in particular, mechanism-based decongestants (McLeod et al, 1999(McLeod et al, , 2001b. These receptors prejunctionally modulate sympathetic neurotransmission and attenuate a variety of organ responses governed by sympathetic nervous system regulation (Koss and Hey, 1992;McLeod et al, 1993;Yu et al, 2001).…”

mentioning

confidence: 99%

Pharmacological Characterization of the Novel Histamine H₃-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

McLeod¹,

Rizzo²,

West³

et al. 2003

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We present the pharmacological and pharmacokinetic profiles of a novel histamine H 3 receptor antagonist, N- (3,phenyl]-methyl]-urea (SCH 79687). The H 3 -receptor binding K i values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The K i values for SCH 79687 at histamine H 1 and H 2 receptors were greater than 1 M. SCH 79687 showed a 41-and 82-fold binding selectivity for the H 3 receptor over ␣ 2A -adrenoceptors and imidazoline I 2 , and Ͼ500-fold H 3 selectivity compared with over 60 additional receptors. The pA 2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 Ϯ 0.3. Similar H 3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pK b ϭ 9.4 Ϯ 0.3 and 10.1 Ϯ 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFSinduced contractions in HSV. SCH 79687 (ED 50 ϭ 0.3 mg/kg i.v.) attenuated (R)-␣-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H 1 -antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The ␣-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H 3 /H 1 combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma C max and area under the curve values greater than 1.5 and 12.1 g ⅐ h/ml, respectively. SCH 79687 is an orally active H 3 antagonist with a good pharmacokinetic profile that, in combination with an H 1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.