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Novel 'soft' anticholinergic agents
R H Hammer1, K Amin, Z E Gunes
1College of Pharmacy, J. Hillis Miller Health Center, University of Florida, Gainesville 32610-0497.
Drug Design and Delivery
|February 1, 1988
Summary
Researchers designed new
Area of Science:
- Pharmacology
- Medicinal Chemistry
Background:
- The "soft drug" concept involves designing drugs that metabolize into non-toxic substances after their therapeutic action.
- Atropine, a potent anticholinergic agent, has limitations due to its prolonged effects and potential toxicity.
Purpose of the Study:
- To design and synthesize novel atropine analogs based on the soft drug principles.
- To evaluate the anticholinergic activity and metabolic stability of these novel compounds.
Main Methods:
- Synthesis of aliphatic and cycloaliphatic esters derived from an inactive acidic metabolite of atropine.
- Assessment of anticholinergic activity using carbachol-induced spasms in guinea pig ileum strips.
- In vitro stability studies in human plasma, pH 12 buffer, and rat liver homogenates.
Main Results:
- Designed esters exhibited atropine-like activity and were metabolized to the inactive parent metabolite in rat liver homogenates.
- Peak anticholinergic activity was observed in esters featuring a quaternary group.
- Hydrolysis rates varied, with the fastest occurring in rat liver homogenate; sterically hindered esters showed greater stability.
Conclusions:
- The soft drug approach is effective in creating atropine analogs with predictable metabolism.
- Quaternization of the synthesized esters enhances anticholinergic potency.
- These novel compounds represent a promising strategy for developing safer and more controllable anticholinergic therapeutics.