Design, pharmacokinetic, and pharmacodynamic evaluation of soft anticholinergics based on tropyl alpha-phenylcyclopentylacetate.
Four new soft anticholinergic agents based on tropyl alpha-phenylcyclopentylacetate, 15a, 15b, 18a, and 18b, were designed and synthesized. Receptor binding studies on the cloned human muscarinic receptors indicated that the new soft anticholinergic agents possessed moderate potency as pKi ranged from 6.7 to 7.6. Mydriatic studies in rabbit eyes revealed that the duration of the action of the new soft anticholinergics (8.5-11.0 h) were shorter than that of atropine (about 24 h) under pharmacodynamic equivalent dose, and one of them, 18a, showed even shorter than that of tropicamide. In addition, after unilateral administration, significant dilation of pupil in the control eyes was observed with tropicamide and atropine but not with soft drugs, suggesting the systemic activity of soft drugs was minimal. With their soft nature, the new soft anticholinergics displayed much shorter protective effect against carbachol-induced bradycardia (about 30 min) than atropine (at least 60 min) in rats. In vitro and in vivo pharmacokinetic studies demonstrated that the soft anticholinergics were rapidly hydrolyzed into the corresponding inactive metabolites once they were introduced into the systemic circulation.
Huang
F
F
Center for Drug Discovery, College of Pharmacy, University of Florida, USA.
Wu
W M
WM
Ji
F
F
Juhász
A
A
Bodor
N
N
D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D018680:Cholinergic Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007202:Indicators and Reagents; D008297:Male; D009184:Mydriatics / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D010648:Phenylacetates / Q000737:chemistry*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000187:drug effects
D018680:Cholinergic Antagonists; D007202:Indicators and Reagents; D009184:Mydriatics; D010648:Phenylacetates; D011950:Receptors, Cholinergic; C079302:alpha-phenylcyclopentylacetic acid