Nasal congestion, one of the major disease features of rhinitis, is induced by the filling of venous sinusoids causing mucosal engorgement with resultant obstruction of nasal airflow. The only available drugs that directly target the underlying vascular features driving nasal obstruction are the sympathomimetic α-adrenoceptor agonists due to their vasoconstrictor action. However, standard decongestants are nonselective α-adrenoceptor agonists, which have the potential for side-effects liabilities such as hypertension, stroke, insomnia and nervousness. In the present study, the effects of nonsubtype selective α2-adrenoceptor agonists BHT-920 and PGE-6201204 were evaluated in several isolated nasal mucosa contractile bioassays including dog, pig and monkey, and in a real-time tissue contractility assay using isolated pig nasal explants for BHT-920. The decongestant activity of PGE-6201204 was evaluated in vivo in a cat model of experimental congestion. Our results showed that α2-adrenoceptor agonists (1) contract nasal mucosa of different species, (2) exert a preferential vasoconstrictor effect on the capacitance vessels (veins and sinusoids), and (3) elicit decongestion. In conclusion, a selective α2-adrenoceptor agonist causing constriction preferentially in the large venous sinusoids and veins of nasal mucosa and producing nasal decongestion is expected to show efficacy in the treatment of nasal congestion without the characteristic arterio-constrictor action of the standard nonselective sympathomimetic decongestants.

We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.

(2003). Effects of an α2-Adrenoceptor Agonist in Nasal Mucosa. Archives of Physiology and Biochemistry: Vol. 111, No. 4, pp. 335-336.

Summary 1 Pig nasal mucosal strips were incubated with α‐adrenoceptor antagonists followed by α2‐adrenoceptor agonist concentration–response curves. 2 Contractions elicited by the α2‐adrenoceptor agonists BHT‐920 (pD2 = 6.16 ± 0.07), UK 14,304 (pD2 = 6.89 ± 0.13) and PGE‐6201204 (pD2 = 7.12 ± 0.21) were blocked by the α2‐adrenoceptor antagonist yohimbine (0.1 μm). In contrast, the α1‐adrenoceptor antagonist prazosin (0.03 μm) had no effect on the BHT‐920‐, UK 14,304‐ and PGE‐6201204‐induced contractions, but blocked the contractile response to the α1‐adrenoceptor agonist phenylephrine (pD2 = 5.38 ± 0.04) and the mixed α1‐ and α2‐adrenoceptor agonist oxymetazoline (pD2 = 6.30 ± 0.22). 3 The α2‐adrenoceptor antagonist yohimbine (0.01–0.1 μm, pA2 = 8.04), α2B/C‐adrenoceptor antagonist ARC 239 (10 μm, pKb = 6.33 ± 0.21), α2A/C‐adrenoceptor antagonist WB 4101 (0.3 μm, pKb = 8.01 ± 0.24), α2A‐adrenoceptor antagonists BRL44408 (0.1 μm, pKb = 6.82 ± 0.34) and RX 821002 (0.1 μm, pKb = 8.31 ± 0.35), α2C‐adrenoceptor antagonists spiroxatrine (1 μm, pKb = 7.32 ± 0.32), rauwolscine (0.1 μm, pKb = 8.16 ± 0.14) and HV 723 (0.3 μm, pKb = 7.68 ± 0.14) inhibited BHT‐920‐induced contractions in pig nasal mucosa. 4 The present antagonist potencies showed correlations with binding affinity estimates (pKi) obtained for these antagonists at the human recombinant α2A‐ and α2C‐adrenoceptors (r = 0.78 and 0.83, respectively) and with binding affinity estimates (pKd) obtained in pig native α2A‐ and α2C‐monoreceptor assays (r = 0.85 and 0.78, respectively). No correlation was observed for the α2B‐subtype. 5 In conclusion, contractile responses to phenylephrine, BHT‐920, UK 14,304, PGE‐6201204 and oxymetazoline indicate that α1‐ and α2‐adrenoceptors are present and mediate vasoconstriction in pig nasal mucosa. Furthermore, correlation analysis comparing antagonist potency in pig nasal mucosa with affinities for human recombinant α2‐adrenoceptors and native pig α2‐adrenoceptors suggest that α2A‐ and α2C‐adrenoceptor subtypes constrict pig nasal mucosa vasculature.

Cough is an important defensive pulmonary reflex that removes irritants, fluids or foreign materials from the airways. However, often cough is non-productive and requires suppression. Opioid mu receptor agonists, such as codeine are commonly used as antitussive agents and are among the most widely administered drugs in the world. Codeine suppresses the responsiveness of one or more components of the central reflex pathway for cough and is an efficacious antitussive drug for cough due to diverse aetiologies. However, opioids produce side effects that include sedation, addiction potential and constipation. Therefore, novel cough suppressant therapies should maintain or improve upon the antitussive efficacy profile of opioids. Moreover, these novel therapies should have a safety profile significantly better than current antitussive therapies. Presently, we discuss preclinical findings showing that activation of the 'opioid-like' receptor (NOP(1)) inhibits cough in the guinea pig and cat.

We studied the central and peripheral antitussive effect of ORL(1) receptor activation with nociceptin/orphanin FQ in conscious guinea-pigs. In guinea-pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 microg) given directly into the CNS by an intracerebroventricular (i.c.v.) route inhibited cough elicited by capsaicin exposure by approximately 23, 29 and 52%, respectively. The antitussive activity of nociceptin/orphanin FQ (90 microg, i.c.v.) was blocked by the selective ORL(1) antagonist [Phe(1)gamma(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) (180 microg, i.c.v.) and J113397 (10 mg kg(-1), i.p.) but not by the opioid antagonist, naltrexone (3 mg kg(-1), i.p.). Furthermore, intravenous (i.v.) nociceptin/orphanin FQ (1.0 and 3.0 mg kg(-1)) also inhibited cough approximately by 25 and 42%, respectively. These findings indicate that selective ORL(1) agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough.