Design, synthesis, and pharmacological evaluation of soft glycopyrrolate and its analog

Glycopyrrolate is a quaternary anticholinergic drug. Like for other anticholinergics, the usefulness of this agent is limited by its side effects. In this study, based on the structure of glycopyrrolate, we designed a soft drug, methoxycarbonylphenyl-cyclopentylacetoxy-N,N-dimethyl-3-p yrrolidinium methyl sulfate (SG), and its analog, methoxycarbonylphenylcyclopentyl-acetoxyethyl-N,N,N-trimethylammon ium methyl sulfate (SGA). These soft drugs are expected to be locally active, but systemically inactive in order to increase therapeutic index. SG and SGA were synthesized by (i) carboxylation of methyl phenylcyclopentylacetate, (ii) esterification with N-methyl-3-pyrrolidinol (for SG) or 2-chloro-N,N-dimethylaminoethane (for SGA), and (iii) quarternization with dimethyl sulfate. Receptor binding studies demonstrate that SG has muscarinic subtype selectivity (m3/m2). Guinea pig ileum pA2 assay indicates that activity of SG is moderate, and SG is about ten times more potent than SGA. The in vivo characterization of SG and SGA, both in mydriasis tests and in prevention of carbachol induced bradycardia, supported its soft nature. Applying SG or SGA into rabbit eyes, the dilation of the contralateral (water-treated) pupils was not observed. Glycopyrrolate application, however, caused dilation of the contralateral pupil, indicating a systemic effect of this drug. Cardiac studies were carried out by evaluating the protective effect of soft anticholinergics against carbachol induced bradycardia. The results indicate that SG and SGA were as potent as atropine-MeBr in preventing carbachol induced bradycardia in the rat; however, their durations of action were significantly shorter. In conclusion, the newly synthesized SG and SGA showed soft nature in the body. They are anticholinergics with subtype selectivity and moderate potency, and can be used as topical antiperspirants.