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.
An efficient and highly stereocontrolled approach for the synthesis of the quinuclidine incorpon class="Species">rated 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.
Authors: Paul S Watson; Bin Jiang; Kim Harrison; Nao Asakawa; Patricia K Welch; Maryanne Covington; Nicole C Stowell; Eric A Wadman; Paul Davies; Kimberly A Solomon; Robert C Newton; George L Trainor; Steven M Friedman; Carl P Decicco; Soo S Ko Journal: Bioorg Med Chem Lett Date: 2006-08-23 Impact factor: 2.823
Authors: Steven Richards; Bryan Sorensen; Hwan-Soo Jae; Marty Winn; Yixian Chen; Jiahong Wang; Steven Fung; Katina Monzon; Ernst U Frevert; Peer Jacobson; Hing Sham; J T Link Journal: Bioorg Med Chem Lett Date: 2006-09-26 Impact factor: 2.823
Authors: Guangrong Zheng; Linda P Dwoskin; Agripina G Deaciuc; Seth D Norrholm; Peter A Crooks Journal: J Med Chem Date: 2005-08-25 Impact factor: 7.446