Soft anticholinergics

Further improvement was obtained by using the corresponding ester analogues of methscopolamine (e.g., 7), some of them proved more potent than the similar soft methatropine analogues [79]. The ethyl ester analogue 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. 

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R. H. Hammer, K. Amin, Z. E. Gunes, G. Brouillette, N. Bodor, Novel Soft Anticholinergic Agents , Drug Design Delivery 1988, 2, 207-219. 

G. N. Kumar, R. H. Hammer, N. S. Bodor, Soft Drugs 12 Design, Syntheses and Evaluation of Soft Anticholinergics , Drug Design Discovery 1993,10, 11-21. 

Huang E, Wu WM, Ji F, et al. Design, pharmacokinetic, and pharmacodynamic evaluation of soft anticholinergics based on tropyl alpha-phenylcyclopentylacetate. Pharmazie 2002 57 115-121. 

Soft Anticholinergics Inactive Metabolite-Based Approach, 558... 

Figure 15.18. Design and metabolism of soft anticholinergics based on the inactive metabolite-based approach (64, 69 substitutions at two different positions) and the soft analog approach (73). pAg values shown are for in vitro anticholinergic activity determined by guinea pig ileum assay with carbachol as agonist.

For soft anticholinergics, the inactive metabolite-based approach can also yield a different class of compounds in which the hydrolytically labile ester-containing side-chain is attached to the quaternary nitrogen head (69). A few such compounds derived from methylatropine (71) (186) or glycopyrrolate... 

Figure 3. Design of soft anticholinergics based on the inactive metabolite approach. A few representative soft anticholinergic structures of the methatropine analogue phenylmalonic (3, n = 0, PMTR) and phenylsuccinic series (3. = 1. PSTR). as well as the closely related methscopolamine analogue series (PMSC. PSSC) are also shown together with the antispasmodic p/t2 values determined using in vitro guinea pig ileum assays.

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