Design, pharmacokinetic, and pharmacodynamic evaluation of a new class of soft anticholinergics.
OBJECTIVE
To design and evaluate a new class of soft anticholinergics with subtype selectivity.


METHODS
A new class of soft anticholinergics was designed based on the "inactive metabolite" approach. Four compounds were synthesized. The potency and soft nature of the compounds were evaluated by receptor binding, cardiac, and mydriatic studies. Stability and pharmacokinetic studies were also performed on these newly synthesized soft anticholinergics.


RESULTS
Receptor binding studies of the soft anticholinergics on cloned muscarinic receptors indicated pKi values in the range of 7.5 to 8.9. Two compounds, 9a and 13a, of the series showed muscarinic subtype receptor selectivity (M3/M2). In mydriatic studies, 13a and 13b showed shorter duration of action in the treated eyes than tropicamide. In the control eyes, significant dilation of pupils was found only in rabbits treated with atropine and tropicamide, indicating that the soft anticholinergics lack systemic effects because of their facile hydrolytic deactivation. Consistent with their soft nature, this new class of soft anticholinergics displayed much shorter cardiovascular effects in the carbachol-induced bradycardia (10 to 15 min) in rats than atropine (> 60 min). Stability and pharmacokinetic studies suggested that the new soft anticholinergics were rapidly eliminated from plasma (systemic circulation) after i.v. administration.


CONCLUSIONS
A new class of anticholinergics was designed and synthesized, and the PK/PD evaluation confirmed they were potent "soft" anticholinergics; two of them showed muscarinic receptor subtype selectivity (M3/M2).
Huang
Fenglei
F
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.
Browne
Clinton E
CE
Wu
Whei-Mei
WM
Juhász
Attila
A
Ji
Fubao
F
Bodor
Nicholas
N
D000287:Administration, Topical; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D018678:Cholinergic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D005123:Eye / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009184:Mydriatics / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism; D013997:Time Factors
D001372:Aza Compounds; D018678:Cholinergic Agents; D003510:Cyclohexanes; D009184:Mydriatics; D011976:Receptors, Muscarinic