title: Pulmonary pharmacology of a novel, smooth muscle-selective muscarinic antagonist in vivo.
abstract: The need for a smooth muscle-selective muscarinic antagonist that could provide oral bronchodilator activity with minimal side effects has led to the discovery of 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (NPC-14695). Orally administered NPC-14695 was as potent as albuterol in the prevention of aerosolized carbachol-induced collapse in conscious guinea pigs. After s.c. administration in conscious guinea pigs challenged with aerosolized carbachol, NPC-14695 was more potent in the inhibition of collapse than in the inhibition of salivation or the production of mydriasis. Moreover, NPC-14695 exhibited a greater selectivity for the inhibition of collapse over salivary or pupillary effects than either ipratropium or oxybutynin. NPC-14695 was more M3/M2 selective than diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP) in vivo, which was determined from the reversal of bronchoconstriction and bradycardia after i.v. administration in anesthetized guinea pigs infused with methacholine, but was less potent than ipratropium or 4-DAMP. At increasing equieffective bronchodilator doses of aerosolized ipratropium and intraduodenally administered NPC-14695 in anesthetized guinea pigs infused with methacholine, ipratropium reversed the bradycardia and then produced tachycardia whereas NPC-14695 did not alter the heart rate. At doses that produced 50% of the maximum bronchodilation, 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 equivalent inhibition of salivation and NPC-14695 produced mydriasis. NPC-14695 did not inhibit the bronchoconstriction induced by three other agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Nova Pharmaceutical Corporation, Baltimore, Maryland.
authors.forename: R E
authors.initials: RE
authors.lastname: Howell
authors.forename: K D
authors.initials: KD
authors.lastname: Laemont
authors.forename: M P
authors.initials: MP
authors.lastname: Kovalsky
authors.forename: V C
authors.initials: VC
authors.lastname: Lowe
authors.forename: P P
authors.initials: PP
authors.lastname: Waid
authors.forename: W J
authors.initials: WJ
authors.lastname: Kinnier
authors.forename: L
authors.initials: L
authors.lastname: Noronha-Blob
mesh_terms: D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D003503:Cyclobutanes / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects*; D018727:Muscarinic Antagonists; D009130:Muscle, Smooth / Q000187:drug effects*; D010276:Parasympatholytics / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*
chemical_list: D001993:Bronchodilator Agents; D003503:Cyclobutanes; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010879:Piperazines; C089125:NPC 14695