Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

Amantadine ( 1 ) exerts its anti-Parkinson effects by inhibition of the NMDA associated cation channel and its antiviral activity by inhibition of the M2 protein channel of influenza A viruses. Herein the synthesis, NMDA receptor affinity and anti-influenza activity of analogous propellanamines 3 are reported. The key steps in the synthesis of the diastereomeric propellanamines syn - 3 and anti- 3 are diastereoselective reduction of the ketone 7 with L-Selectride to give anti - 11 , Mitsunobu inversion of the alcohol anti - 13 into syn - 13 , and S N 2 substitution of diastereomeric mesylates syn - 14 and anti - 14 with NaN 3 . The affinity of the propellanamines syn - 3 and anti- 3 to the PCP binding site of the NMDA receptor is similar to that of amantadine ( K i = 11 μM). However, both propellanamines syn - 3 and anti- 3 do not exhibit activity against influenza A viruses. Compared to amantadine ( 1 ), the structurally related propellanamines syn - 3 and anti- 3 retain the NMDA antagonistic activity but loose the antiviral activity.