Synthesis and monoamine transporter affinity of 3-aryl substituted trop-2-enes

A series of new 3-aryl-tropanes have been synthesized, and their affinities and selectivities were evaluated for monoamine transporters. (1RS)-3-(Fluoren-2-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene exhibited the highest affinity for the human serotonin transporter (IC50 = 14.5 nM). It is also 52-fold and 230-fold selective over human dopamine and norepinephrine transporters, respectively.

A 3-aryl-trop-2-ene ligand shown in the tentative binding pocket of a human monamine transporter. Conformational states A–D are dependent on the selection of the aromatic substituent at C3. The red colored electrostatic potential maps reveal the electron rich regions of A–D.Figure optionsDownload as PowerPoint slide