DESIGN AND EVALUATION OF NEW SOFT ANTICHOLINERGIC AGENTS

The design and evaluation of two new soft anticholinergic agents, bony lphenylcyclopentylacetyl-N,N-dimethyltropinium methyl sulfate (PCMS-1) and bonylphenylcyclopentylacetyl-N,N-dimethyltropinium methyl sulfate (PCMS-2) are presented. According to the inactive metabolite approach of the soft drug design and using methatropine as the lead compound, the corresponding ethyl- and methylesters were formed and a cyclopenty l ring was also introduced in the structures. By the latter, the enhan cement of anticholinergic activity was expected based on previous expe rience. However, this was not fully achieved, as both receptor binding studies and pA(2) values showed a somewhat lower in vitro activity of PCMS-1 and PCMS-2 than that of tematropium. This was probably due to the increase of the volume of the molecules by the cyclopentyl ring, a s demonstrated by quantitative structure-activity relationship calcula tions. According to these, molecular size is a very important activity determining factor. The in vivo characterization of PCMS-2, both in t he mydriasis tests and in the prevention of carbachol-induced bradycar dia, supported its soft nature. Applying PCMS-2 into rabbit eyes, dila tion of the contralateral pupils was not observed. Both methatropine ( at all concentrations applied) and tropicamide (at 1%) caused dilation of the contralateral pupils, indicating a systemic effect of these re ference drugs. PCMS-2 was as potent as methatropine in preventing carb achol-induced bradycardia in the rat; however, its duration of action was significantly shorter, 15-30 min vs. 2 h, respectively. (C) 1998 W iley-Liss, Inc.