2-BETA-SUBSTITUTED ANALOGS OF 4'-IODOCOCAINE - SYNTHESIS AND DOPAMINETRANSPORTER BINDING POTENCIES

A series of 2 beta-substituted analogues of 4'-iodococaine (3) was syn thesized and evaluated in an in vitro dopamine transporter (DAT) bindi ng assay. Selective hydrolysis at the 2 beta-position of 3 gave the ca rboxylic acid 15 that served as the intermediate for the synthesis of compounds 4, 5, and 6-11. The 2 beta-alkyl derivatives were obtained f rom ecgonine methyl ester (17) through a series of reactions leading t o the aldehyde 20, Wit-tig reaction of 20 with methyltriphenylphosphor ane followed by hydrogenation and benzoylation gave the products 12 an d 13. The binding affinity of 4'-iodococaine (3) was 10-fold less than that of cocaine. The hydroxymethane, acetate, amide, benzyl ester, ox idazole, and ethane derivatives of 3 exhibited decreased binding while the vinyl, phenyl, and ethyl esters showed a moderate increase in bin ding affinity. Only the isopropyl derivative 8 exhibited a 2-fold incr ease in binding affinity compared with 4'-iodococaine (3). Hydroxylati on of 8 at the 2'-position gave 14 which enhanced not only the binding potency at the DAT by another 2-fold but also the selectivity at the DAT over the norepinephrine and serotonin transporters. Compound 14 fa iled to stimulate locomotor activity in C57BL/6J mice over a wide dose range and blocked cocaine-induced locomotor stimulant action.