Pyrrolidine analogues of lobelane: Relationship of affinity for the dihydrotetrabenazine binding site with function of the vesicular monoamine transporter 2 (VMAT2)

Ring size reduction of the central piperidine ring of lobelane yielded pyrrolidine analogues that showed marked inconsistencies in their ability to bind to the dihydrotetrabenazine (DTBZ) binding site on the vesicular monoamine transporter-2 (VMAT2) and their ability to inhibit VMAT2 function. The structure-activity relationships indicate that structuralmodification within thepyrrolidine series resulted in analogues that interactwith two different sites, i.e., the DTBZ binding site and an alternative site on VMAT2 to inhibit transporter function.