Design and evaluation of new soft anticholinergic agents

Abstract

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 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, 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. Drug Dev. Res. 43:117-127, 1998. © 1998 Key words: drug design; metabolism; drug evaluation; muscarinic antagonists

Receptor binding studies of soft anticholinergic agents

“…Hence, it represents a size and shape descriptor, as it depends on the shape of the molecule and, for common organic molecules, it also scales with size. Our previous 2 structureactivity relationship studies already indicated an important role played by molecular size in this class of soft anticholinergics (9,53). In the present study, molecular size as measured, for example, by volume is still highly correlated with muscarinic binding activity in the analyzed 3 receptor subtypes; however, ovality (O e ) seems to be somewhat more relevant.…”

“…On the basis of previous studies (9,10), the most labile soft anticholinergics from each series of soft anticholinergics were chosen to test the integrity of the compound during incubation with the esterase enzyme inhibitor. AQC, PMTR.Et, PCMS-1, PCDT, and PCTM were chosen to test the stability in the receptor media.…”

“…Even topical applications of anticholinergics can lead to unwanted systemic side effects because of their absorption and drainage into the systemic circulation. In a series of attempts to separate desired therapeutic effects from toxic effects⎯that is, to improve the therapeutic index⎯several series of novel anticholinergic agents have been designed, synthesized, and tested in our laboratories since the early 1980s based on soft drug design approaches (8)(9)(10).…”

“…By incorporating an adequate metabolically labile moiety into their structure, they can be potent and locally active as anticholinergic agents, but with only minimal systemic anticholinergic effects due to their rapid metabolism in the systemic circulation. Thus, the overall therapeutic index is greatly improved (9,10).…”

Soft drug design: General principles and recent applications

“…65 This compound was shorter acting than even tropicamide, and, consistent with the soft drug approach, the untreated eye did not show any mydriasis, as opposed to administration of methscopolamine. Other structures like the cyclopentyl derivative 16 (PCMS-2) 64 or different phenylsuccinic analogues of methatropine 63 and methscopolamine 66 were also investigated. As recently shown, 16 was equipotent to atropine in protecting against carbachol-induced bradycardia in rats, but the duration of action was again significantly shorter (15-30 min vs. more than 2 h) ( Fig.…”