title: RWJ-22108--a novel airway tissue--selective calcium channel blocker.
abstract: RWJ-22108 is a novel calcium entry blocker that has potential therapeutic use as an antiasthmatic agent. Although displaying typical potent inhibition of 45Ca uptake into aortic rings (IC50 = 7.1 nM) and displacement of [3H]nitrendipine from cardiac membranes (IC50 = 137 nM), RWJ-22108 demonstrates tissue selectivity in the inhibition of KCl-induced contractions. RWJ-22108 inhibits the calcium-dependent contraction of canine bronchiolar smooth muscle with an IC50 of 5.7 nM. The IC50 femoral artery/IC50 bronchiolar ratios are 2.85, 8.02, 1.47 and 1.96 for nifedipine, RWJ-22108, verapamil, and gallopamil, respectively. Furthermore, this selectivity ratio (range 2.8-5.5) of RWJ-22108 is also observed when inhibition of other pulmonary and cardiovascular smooth muscles are compared. Using canine tracheal muscle and rabbit aortae, the IC50 aorta/IC50 trachea ratio is 1.75 for RWJ-22108 compared to approximately 0.5 for several calcium blocker standards. These results indicate that in vitro RWJ-22108 is a bronchoselective calcium channel blocker.
authors.affiliation: R.W. Johnson Pharmaceutical Research Institute, Department of Experimental Therapeutics, Raritan, NJ 08869.
authors.forename: J B
authors.initials: JB
authors.lastname: Moore
authors.forename: W C
authors.initials: WC
authors.lastname: Miller
authors.forename: S
authors.initials: S
authors.lastname: Mockoviak
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D002132:Calcium Radioisotopes; D004285:Dogs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009568:Nitrendipine / Q000493:pharmacokinetics; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D012137:Respiratory System / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D011725:Pyridines; C080337:RWJ 22108; D011189:Potassium Chloride; D009568:Nitrendipine; D002118:Calcium