PULMONARY PHARMACOLOGY OF A NOVEL, SMOOTH MUSCLE-SELECTIVE MUSCARINICANTAGONIST IN-VIVO

The need for a smooth muscle-selective muscarinic antagonist that coul d provide oral bronchodilator activity with minimal side effects has l ed to the discovery of zinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propan one (NPC-14695). Orally administered NPC-14695 was as potent as albute rol in the prevention of aerosolized carbachol-induced collapse in con scious guinea pigs. After s.c. administration in conscious guinea pigs challenged with aerosolized carbachol, NPC-14695 was more potent in t he inhibition of collapse than in the inhibition of salivation or the production of mydriasis. Moreover, NPC-14695 exhibited a greater selec tivity for the inhibition of collapse over salivary or pupillary effec ts than either ipratropium or oxybutynin. NPC-14695 was more M(3)/M(2) selective than diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP ) in vivo, which was determined from the reversal of bronchoconstricti on and bradycardia after i.v. administration in anesthetized guinea pi gs infused with methacholine, but was less potent than ipratropium or 4-DAMP. At increasing equieffective bronchodilator doses of aerosolize d ipratropium and intraduodenally administered NPC-14695 in anesthetiz ed guinea pigs infused with methacholine, ipratropium reversed the bra dycardia and then produced tachycardia whereas NPC-14695 did not alter the heart rate. At doses that produced 50% of the maximum bronchodila tion, neither aerosolized ipratropium or intraduodenally administered NPC-14695 affected the pupillary diameter or salivation. At doses that produced a maximum bronchodilation, the two drugs produced an equival ent inhibition of salivation and NPC-14695 produced mydriasis. NPC-146 95 did not inhibit the bronchoconstriction induced by three other agon ists. In conclusion, NPC-14695 appears to exhibit a smooth muscle musc arinic receptor subtype selectivity in vivo that may provide oral bron chodilator activity with minimal side effects for the treatment of obs tructive airway disease.