COCAINE AND 3-BETA-(4'-SUBSTITUTED PHENYL)TROPANE-2-BETA-CARBOXYLIC ACID ESTER AND AMIDE ANALOGS - NEW HIGH-AFFINITY AND SELECTIVE COMPOUNDS FOR THE DOPAMINE TRANSPORTER

Several 2 beta-carboxylic acid ester and amide analogues of cocaine an d of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid were prepared. The binding affinities of these compounds, and of some prev iously prepared analogues, at the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters were determined. The phenyl esters o f 3 beta-(4'-methylphenyl)and 3 beta-(4'-chlorophenyl)trop ane-2 beta- carboxylic acid are highly potent and highly selective for the DA tran sporter. The isopropyl esters of 3 beta-(4'- chlorophenyl)- and 3 beta -(4'-iodophenyl)tropane-2 beta-carboxylic acid also possess high DA af finity and show significant DA transporter selectivity. Similarly, the phenyl and isopropyl ester analogues of cocaine are much more selecti ve for the DA transporter than cocaine. Tertiary amide analogues of co caine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic a cids are more potent inhibitors of radioligand binding at the DA trans porter than the primary and secondary amide analogues. In particular, 3 beta-(4'-chlorophenyl)tropane-2 beta-N-morpholinocarboxamide as well as the 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-N-pyrrolidinocarboxamides possess high affinity and selectivity f or the DA transporter. The N,N-dimethylamide cocaine analogue is the m ost selective cocaine amide derivative for the DA transporter. High co rrelation between the inhibition of radioligand binding and inhibition of uptake at the DA, NE, and 5-HT transporter was found for a selecte d group of analogues. Within this group, one compound, the isopropyl e ster of 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid, was foun d to be more potent in the inhibition of radioligand binding than in t he inhibition of DA uptake. Taken together with its high potency and s electivity at the DA transporter, this suggests that this compound may be a lead in the development of a cocaine antagonist.