Cholinergic compounds. II - Synthesis and biological activity of epi- and allo-desethermuscarines

To obtain further clarification of structure-activity relationships of cholinergic substances, which would give better understanding of cholinergic receptors, the carbocyclic analogs of epi-muscarine (I) and allo-muscarine (II) were prepared starting from 6-methyl-3-oxo-2-oxabicyclo[2.2.1]heptane (IV). Pharmacological tests show that these two compounds possess lower muscarinic activity than the carbocyclic analog of muscarine (desethermuscarine), the allo isomer being from 5 to 500 times more active than the epi isomer. Therefore, the activity in the carbocyclic series follows, for these receptors, the same pattern as the oxygenated one. As far as nicotinic activity is concerned. (I) is 2.5 times more active than (II), the effective doses being from 40 to 100 times higher than that of Ach. These results suggest a steric rather than an electronic influence for the ether oxygen, whose principal role seems to be that of contributing to the rigidity of the molecule. For most receptors assayed, an inverse relationship between the potency ratio of the isomers and the sensitivity towards Ach has been observed.