No abstract

To reduce the possibility of systemic side-effects in locally administered anticholinergics, two new N-substituted glycopyrrolate analogues designed using soft drug design approaches have been synthesized and evaluated in vitro and in vivo. Because stereospecificity is known to be important at muscarinic receptors, the new compounds SGM and SGE also have been prepared as their pure 2R isomers, 2R-SGM and 2R-SGE, by starting from optically pure (-)-cyclopentylmandelic acid, and the corresponding isomers were indeed found to be more active. The new soft glycopyrrolates were chemically more stable under acidic conditions, and the ethyl esters SGE were more stable than the methyl esters SGM. The new compounds were also found to be quite susceptible to extrahepatic metabolism, having half-lives of 20-30 min in rat plasma (in vitro), consistent with their soft nature. Binding studies at human muscarinic receptors (M(1)-M(4)) and guinea-pig ileum assays found 2R-SGM and 2R-SGE to have potencies somewhat less than, but close to, those of glycopyrrolate and N-methylscopolamine. They caused pupil dilation in rabbit eyes, but their mydriatic effects lasted for considerably less time than that of glycopyrrolate, and they did not induce dilation of the pupil in the contralateral, water-treated eyes, indicating that, in agreement with their soft nature, they are locally active, but safe and with a low potential to cause systemic side-effects.

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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

Triazolo[6,7‐d]phthalide has been synthesized in a seven step sequence from phthalide in 24% overall yield, and triazolo[6,7‐d]dihydrocoumarin has been prepared in nine steps from dihydrocoumarin in 20% overall yield. The 1H and 13C nmr spectra and the tautomeric equilibria of the final compounds and intermediates are discussed.