SYNTHESIS AND LIGAND-BINDING STUDIES OF 4'-IODOBENZOYL ESTERS OF TROPANES AND PIPERIDINES AT THE DOPAMINE TRANSPORTER

Four analogs and two homologs of cocaine, designed as potent cocaine a ntagonists, were synthesized. The S(N)2 reaction between ecgonine meth yl ester (13) or appropriately substituted piperidinol (19, 21) and ap propriately substituted 4-iodobenzoyl chloride gave 4-iodobenzoyl este rs of tropanes and piperidines (5-8). 2'-Hydroxycocaine (9) was obtain ed from 2'-acetoxycocaine (12) by selective transesterification with M eOH saturated with dry HCl gas. 2'-Acetoxycocaine (12) was synthesized from acetylsalicyloyl chloride (23) and ecgonine methyl ester (13). T he binding affinities of these compounds were determined at the dopami ne transporter for the displacement of [H-3]WIN-35428. An iodo group s ubstitution at the 4'-position of cocaine decreased dopamine transport er binding potency, while a hydroxy or acetoxy group at the 2'-positio n exhibited increased binding potency for the dopamine transporter com pared to cocaine (10- and 3.58-fold, respectively). 2'-Hydroxylation a lso enhanced the binding potency of 4'-iodococaine (5) by 10-fold. Rep lacement of the tropane ring with piperidine led to poor binding affin ities.