HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Binary antidotes for organophosphate poisoning: aprophen analogues that are both antimuscarinics and carbamates.

Abstract
Prophylaxis against organophosphate poisoning can be achieved by pretreatment with physostigmine or pyridostigmine, which are carbamates, and aprophen, which is an anticholinergic agent. Thus, a series of aprophen analogues was synthesized with carbamyl substitutions on the phenyl rings (carbaphens). The rationale behind this design is that such compounds might exhibit most of the therapeutic characteristics of aprophen, as well as the ability to protect prophylactically by chemically masking cholinesterase enzymes. Compounds 4 (dimethylhydroxycarbaphen), 15 (dimethylcarbaphen), and 16 (monomethylcarbaphen) were found to inactivate human butyrylcholinesterase in a time-dependent manner with potencies similar to those of physostigmine or pyridostigmine, and the latter two exhibited almost the same antimuscarinic profile as aprophen. In contrast to the potent inactivation of butyrylcholinesterase by these compounds, marginal inactivation of acetylcholinesterase activity was observed, and only at much higher drug concentrations. The noncarbamylated analogues had no effect on the activity of either cholinesterase. The carbaphen compounds are hence prototype drugs that can interact with either muscarinic receptors or butyrylcholinesterase. Furthermore, these compounds are prodrugs, since after carbamylation of the cholinesterase, the leaving group 14 (hydroxyaprophen) is a potent antimuscarinic itself.
AuthorsH Leader, R M Smejkal, C S Payne, F N Padilla, B P Doctor, R K Gordon, P K Chiang
JournalJournal of medicinal chemistry (J Med Chem) Vol. 32 Issue 7 Pg. 1522-8 (Jul 1989) ISSN: 0022-2623 [Print] United States
PMID2738887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antidotes
  • Carbamates
  • Cholinesterase Inhibitors
  • Parasympatholytics
  • Phenylpropionates
  • aprofen
Topics
  • Animals
  • Antidotes
  • Carbamates
  • Chemical Phenomena
  • Chemistry
  • Cholinesterase Inhibitors
  • Guinea Pigs
  • In Vitro Techniques
  • Kinetics
  • Male
  • Organophosphate Poisoning
  • Parasympatholytics
  • Phenylpropionates (pharmacology)
  • Rats
  • Rats, Inbred Strains

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: