Design and evaluation of new soft anticholinergic agents

The design and evaluation of two new soft anticholinergic agents, ethoxycarbonylphenylcyclopentylacetyl-N,N-dimethyltropinium methyl sulfate (PCMS-1) and methoxycarbonylphenylcyclopentylacetyl-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 cyclopentyl ring was also introduced in the structures. By the latter, the enhancement of anticholinergic activity was expected based on previous experience. However, this was not fully achieved, as both receptor binding studies and pA₂ 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, as demonstrated by quantitative structure- activity relationship calculations. According to these, molecular size is a very important activity determining factor. The in vivo characterization of PCMS-2, both in the mydriasis tests and in the prevention of carbachol- induced bradycardia, supported its soft nature. Applying PCMS-2 into rabbit eyes, dilation 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 reference drugs. PCMS-2 was as potent as methatropine in preventing carbachol-induced bradycardia in the rat; however, its duration of action was significantly shorter, 15-30 min vs. 2 h, respectively.