6-Methyl-6-azabicyclo[3.2.1]octan-3.alpha.-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent

Authors:
  • FCF. Ivy Carroll
    F. Ivy Carroll
  • PAPhilip Abraham
    Philip Abraham
  • KPKarol Parham
    Karol Parham
  • RGRonald C. Griffith
    Ronald C. Griffith
  • AAAteeq Ahmad
    Ateeq Ahmad
  • MRMichelle M. Richard
    Michelle M. Richard
  • FPFelipe N. Padilla
    Felipe N. Padilla
  • JWJeffrey M. Witkin
    Jeffrey M. Witkin
  • PCPeter K. Chiang
    Peter K. Chiang
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Abstract
The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3.alpha.-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block .alpha.-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.

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