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

Glycopyrrolate is a quaternary anticholinergic drug. Like for other anticho linergics, the usefulness of this agent is limited by its side effects. In this study, based on the structure of glycopyrrolate, we designed a soft dr ug, methoxycarbonylphenylcyclopentylacetoxy-N,N-dimethyl-3-pyrr olidinium m ethyl sulfate (SG), and its analog, methoxycarbonylphenylcyclopentylacetoxy ethyl-N, N,N-trimethylammonium methyl sulfate (SGA). These soft drugs are e xpected to be locally active, but systemically inactive in order to increas e therapeutic index. SG and SGA were synthesized by (i) carboxylation of me thyl phenylcyclopentylacetate, (ii) esterification with N-methyl-3-pyrrolid inol (for SG) or 2-chloro-N,N-dimethylaminoethane (for SGA), and (iii) quar ternization with dimethyl sulfate. Receptor binding studies demonstrate tha t SG has muscarinic subtype selectivity (m(3)/m(2)) Guinea pig ileum pA(2) 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 m ydriasis tests and in prevention of carbachol induced bradycardia, supporte d its soft nature. Applying SG or SGA into rabbit eyes, the dilation of the contralateral (water-treated) pupils was not observed. Glycopyrrolate appl ication, however, caused dilation of the contralateral pupil, indicating a systemic effect of this drug. Cardiac studies were carried out by evaluatin g the protective effect of soft anticholinergics against carbachol induced bradycardia. The results indicate that SG and SGA were as potent as atropin e-MeBr in preventing carbachol induced bradycardia in the rat; however, the ir durations of action were significantly shorter In conclusion, the newly synthesized SG and SGA showed soft nature in the body. They are anticholine rgics with subtype selectivity and moderate potency, and can be used as top ical antiperspirants.