Stereocontrolled synthesis and pharmacological evaluation of cis-2,6-diphenethyl-1-azabicyclo[2.2.2]octanes as lobelane analogues.

An efficient and highly stereocontrolled approach for the synthesis of the quinuclidine incorporated lobelane analogues, endo,endo- and exo,exo-2,6-cis-diphenethyl-1-azabicyclo-[2.2.2]octane (2 and 3), has been developed. Analogues 2 and 3 were designed to mimic the axial and equatorial geometry, respectively, of the vesicular monoamine transporter-2 (VMAT2) inhibitor, lobelane. The exo,exo analogue 2 had comparable affinity to lobelane and had greater affinity than the endo,endo analogue 3 at the tetrabenazine binding site on VMAT2, indicating that the preferred binding mode of lobelane is likely the extended conformation.