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.
Zheng
Guangrong
G
College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
Dwoskin
Linda P
LP
Deaciuc
Agripina G
AG
Crooks
Peter A
PA
D000818:Animals; D001665:Binding Sites; D034242:Cyclooctanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008120:Lobeline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D051381:Rats; D013237:Stereoisomerism; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D034242:Cyclooctanes; D050493:Vesicular Monoamine Transport Proteins; C540157:lobelane; D008120:Lobeline