Crystal, Solution, and Molecular Modeling Structural Properties and Muscarinic Antagonist Activity of Azaprophen

The structure of azaprophen, which was originally assigned by¹H NMR analysis, was confirmed by X-ray crystallography. A comparison of ¹³C NMR isotropic chemical shift data for azaprophen in the solid state and in CDC1₃and DMSO-d₆ solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m₁ and m₃ receptors was conducted. Azaprophen is more active than atropine in all preparations except the m₃ receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.