Structure–activity studies of 3′-4′-dichloro-meperidine analogues at dopamine and serotonin transporters

The structure–activity relationships of 3′,4′-dichloro-meperidine were investigated at dopamine (DAT) and serotonin transporters (SERT). Large ester substituents and lipophilic groups at the 4-position favored molecular recognition at the SERT. The benzyl ester of 3′,4′-dichloro-meperidine exhibited high potency and high selectivity for the SERT (DAT/SERT = 760). Chemical modification of the ester group and N-substitution generally led to compounds with decreased DAT affinity. Only small esters and alkyl groups were tolerated at the 4-position of the meperidine ring system by the DAT. Overall, the meperidine analogues were generally more selective for the SERT than for the DAT

Synthesis, dopamine and serotonin transporter binding affinities of novel analogues of meperidine

A series of meperidine analogues was synthesized and the binding affinities for the dopamine and serotonin transporters were determined. The substituents on the phenyl ring greatly influenced the potency and selectivity of these compounds for the transporter binding sites. In general, meperidine ( 3) and its analogues were more selective for serotonin transporter binding sites and the esters 9 were more potent than the corresponding nitriles 8. The 3,4-dichloro derivative 9e was the most potent ligand of the series for dopamine transporter binding sites while the 2-naphthyl derivative 9g exhibited the most potent binding affinity and was highly selective for serotonin transporter binding sites. A series of meperidine analogues was synthesized and the binding affinities for the dopamine and serotonin transporters were determined

Synthesis, Structure, Dopamine Transporter Affinity, and Dopamine Uptake Inhibition of 6-Alkyl-3-benzyl-2-[(methoxycarbonyl)methyl]tropane Derivatives

A series of 6-alkyl-3β-benzyl-2-[(methoxycarbonyl)methyl]tropane analogues were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter (DAT). The in vitro affinity (K i) for the DAT of the 6-alkyl-3β-benzyl-2-[(methoxycarbonyl)methyl]tropane analogues was determined by inhibition of [3H]WIN 35,428 in rat caudate putamen tissue. The inhibition of dopamine uptake (IC50) was also measured for selected compounds which demonstrated moderate affinity for the dopamine transporter. The unsubstituted enantiopure analogues (−)-19a (K i = 33 nM) and surprisingly (+)-20a (K i = 60 nM) were found to be almost equipotent with the high-affinity binding components of cocaine and WIN 35,065-2 and exhibited slightly more potent dopamine uptake inhibition than both cocaine and WIN 35,065-2. In general, substitution at the 6-position of racemic 19a and 20a with alkyl groups was found to result in decreased activity relative to increased chain length of the substituent. The 3β-benzyl-2β-[(methoxycarbonyl)methyl]-6β-methyltropane (21b; K i = 57 nM) was the only 6-alkyl derivative to exhibit moderately potent activity. The 6β-isomer 21b was 4-fold more potent than the 6α-isomer 19b (K i = 211 nM) and was nearly equipotent with (−)-19a and (+)-20a as well as with cocaine and WIN 35,065-2. The results of this study further demonstrate the steric constraints associated with the C(6)−C(7) methylene bridge of the tropane ring system for molecular recognition of cocaine analogues at the cocaine binding site(s) on the DAT

Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-Substituted 3β-Phenyltropane Derivatives

A series of 2β-substituted 3β-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with high affinity (K i = 11−22 nM) to the dopamine transporter. Increased lipophilicity at the β-C(2)-position was found to lead to increased binding affinity and increased dopamine uptake potency. However, a direct correlation between clogP values and binding affinity and potency of uptake inhibition was not observed. The unsaturated ester 7 was found to possess weak dopamine uptake inhibition relative to the high binding affinity (IC50/K i = 10.2). In vivo measurement of stimulated locomotor activity and drug discrimination against cocaine (10 mg/kg, ip) with selected analogs (4, 6, and 7) demonstrated that the behavioral effects of these drugs were approximately equipotent with those of cocaine. The structure−activity relationships of this series of cocaine analogs supports a pharmacophore model in which lipophilic interactions between the β-C(2)-position of 3β-phenyltropanes and the cocaine binding site on the dopamine transporter lead to enhanced potency while electrostatic interactions have a nonspecific effect