Synthesis and Muscarinic Receptor Activity of Ester Derivatives of 2-Substituted 2-Azabicyclo[2.2.1]heptan-5-ol and -6-ol

Radioligand binding affinities of four new muscarinic antagonists and six potential muscarinic agonists which possess the 2-alkyl-2-azabicyclo[2.2.1]heptane ring system have been determined in rat heart, rat brain, and m₁ or m₃-transfected CHO cell membrane preparations to examine the selectivity for subtypes of muscarinic receptor. The efficacies of the potential muscarinic agonists were determined by the ratio of binding affinities against [³H]QNB and [³H]Oxo-M. Four muscarinic antagonists which have the 2,2-diphenylpropionate side chain at either the C₅ (5-endo or 5-exo) or the C₆ (6-endo or 6-exo) positions did not discriminate between the subtypes of muscarinic receptors. The 2,2-diphenylpropionate 5-endo substituted compound was the most potent, showing affinities between 4.23 × 10^-10 and 1.18 × 10^-9 M in rat heart, rat brain, and m₁ or m₃-transfected CHO cell membrane preparations. The rank order of ester potency was 5-endo > 5-exo > 6-endo > 6-exo. A molecular modeling study based on the pharmacophore developed for azaprophen was used to account for the relative potency of these antagonists. Six potential muscarinic agonists which have acetoxy groups in the C₅ or C₆ position with an N-methyl or N-benzyl substituent did not discriminate subtypes of muscarinic receptors and had affinities between 6.63 × 10^-6 and 4.76 × 10^-5 M in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations. exo-2-Methyl-5- acetoxy-2-azabicyclo[2.2.1]heptane was the most efficacious partial agonist.