benzofurans and Cough

Studies performed in healthy smokers have documented a diminished responsiveness to tussive challenges, and several lines of experimental evidence implicate nicotine as an antitussive component in both cigarette smoke and the vapors generated by electronic cigarettes (eCigs). We set out to identify the nicotinic receptor subtype involved in the antitussive actions of nicotine and to further evaluate the potential of nicotinic receptor-selective agonists as cough-suppressing therapeutics. We confirmed an antitussive effect of nicotine in guinea pigs. We additionally observed that the alpha-4 beta-2 (

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Antitussive Agents; Benzofurans; Cough; Guinea Pigs; Male; Nicotine; Nicotinic Agonists; Quinuclidines

A significant population of patients with severe asthma and chronic obstructive pulmonary disease is less responsive to beta(2)-adrenoceptor agonists and corticosteroids, and there are possible safety issues concerning long-term use of these drugs. Inhaled prostaglandin E(2) (PGE(2)) is antiinflammatory and a bronchodilator in patients with asthma, but it also causes cough.. We aimed to identify the receptor involved in PGE(2)-induced sensory nerve activation and cough using a range of in vitro and in vivo techniques.. Depolarization of vagal sensory nerves (human, mouse, and guinea pig) was assessed as an indicator of sensory nerve acitivity. Cough was measured in a conscious guinea pig model.. Using an extensive range of pharmacological tools, we identified that the EP(3) receptor mediates PGE(2)-induced depolarization of sensory nerves in human, mouse, and guinea pig. Further supporting evidence comes from data showing that responses to PGE(2) are virtually abolished in isolated vagus nerves from EP(3)-deficient mice (Ptger3(-/-)). Finally, we demonstrated the role of the EP(3) receptor in vivo using a selective EP(3) antagonist to attenuate PGE(2)-induced cough.. Identification of the receptor mediating PGE(2)-induced cough represents a key step in developing a drug that is antiinflammatory and a bronchodilator but without unwanted side effects.

Topics: Animals; Benzofurans; Cough; Cyclopentanes; Dimethyl Sulfoxide; Dinoprostone; Guinea Pigs; Humans; In Vitro Techniques; Isoindoles; Male; Mice; Mice, Inbred C57BL; Propionates; Pyridines; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype; Sensory Receptor Cells; Sulfonamides; Vagus Nerve; Xanthones

A patient with atrial premature depolarizations developed pulmonary toxicity during long-term treatment with amiodarone. The clinical features were cough and dyspnea. Pulmonary function tests showed a restrictive defect and severe impairment of gas transfer. Diffuse interstitial and intra-alveolar shadows were noted on chest X-ray. Lung specimens obtained by transbronchial biopsy showed hyperplasia of pneumocytes and widening of the alveolar septa. After discontinuation of amiodarone and institution of steroid therapy the patient improved symptomatically, and after 3 weeks the chest X-ray showed clearing of the bilateral infiltrates. The patient was never given any other antiarrhythmic drugs, had no important heart disease, and received the lowest daily dose of amiodarone reported in the literature of cases of pulmonary injury.

Topics: Amiodarone; Benzofurans; Cough; Dyspnea; Female; Humans; Middle Aged; Pulmonary Fibrosis; Respiratory Function Tests

The antitussive effect of the new compound 1, 2, 3, 4a, 9b-hexahydro-8, 9b-dimethyl-4-[3-(4-methyl-piperazine-1-yl) propionamide] dibenzofuran-3-one dihydrochloride (RU-20201) was investigated in dogs and guinea pigs, including its sites of action. The antitussive effect of RU-20201 was about 1/10 as potent as that of codeine phosphate in dogs with the puncture electrode-induced cough (PEC) method and about 1/12 and 1/4 as potent as that of codeine phosphate in guinea pigs with the PEC and chemical stimulation methods, respectively. When RU-20201 was administered in a dose range of 1 to 10 mg into the vertebral artery toward the brain in lightly anesthetized dogs, no antitussive effect was observed against the coughing elicited by electrical stimulation of the central cut end of the superior laryngeal nerve. However, a stimulative effect on respiration, especially on respiratory rate occurred. The peripheral effect of RU-20201 on the cough was investigated using the in situ upper trachea perfusion preparation which allows a direct drug administration to the local site around the tracheal mucosa, this site being electrically stimulated to induce coughing. A close i.a. infusion of RU-20201 in doses of 1 and 3 mg/min into the tracheal vascular bed for 5 min inhibited the cough response elicited by mucosal stimulation. The above findings suggest that RU-20201 has a significant antitussive activity, the site of action being probably, at least, at the cough receptor level.

Topics: Animals; Antitussive Agents; Benzofurans; Codeine; Cough; Dogs; Electric Stimulation; Guinea Pigs; Injections, Intra-Arterial; Male; Procaine; Respiration; Sensory Receptor Cells; Species Specificity; Sulfur Dioxide; Vertebral Artery

The effect of the drug Ru 20201 (1,2,3,4,4a,9b-hexahydro,-8,9b-dimethyl-4-[3-(4-methylpiperazin-1-yl)propionamido]dibenzofuran-3-one upon mechanically-evoked cough from the laryngopharyngeal and tracheobronchial areas in nine unanaesthetized cats has been examined. Inhalation of 2 ml of an aerosol of a 10% solution in water suppressed coughing for 30 min. The effect was greatest on the number of cough efforts. The expiratory component of cough was suppressed more than was the inspiratory one. The effect was greater on cough from the laryngopharyngeal than from the tracheobronchial area.

Topics: Aerosols; Animals; Antitussive Agents; Benzofurans; Bronchi; Cats; Cough; Female; Larynx; Male; Pharynx; Physical Stimulation; Piperazines; Trachea

The synthesis of a novel series of antitussive agents is described. Two series of amino-substituted tetra- and hexahydrodibenzofurans were prepared and examined for antitussive activity in the guinea pig after cough elicited by electrical stimulation of the vagus nerve. A significant level of activity, comparable with that of codeine, was found in the 4alpha-amino series. The 4-methylpiperazin-1-ylpropionamide (28) was found to be the most active of the compounds synthesized and was equipment with codeine. The effects of structural modification upon antitussive activity were investigated in numerous analogues but no enhancement of activity was achieved over that of 28.

Topics: Animals; Antitussive Agents; Benzofurans; Cough; Electric Stimulation; Guinea Pigs; Male; Structure-Activity Relationship; Vagus Nerve