Development of Novel, Potent, and Selective Dopamine Reuptake Inhibitors through Alteration of the Piperazine Ring of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)

Abstract

The design, synthesis, and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors: 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12395 and GBR 12909, respectively), directed toward the development and identification of new ligands interacting with high potency and selectivity at the dopamine transporter (DAT) is reported. The substitution of the piperazine ring in the GBR structure with other diamine moieties resulted in the retention of the high affinity of new ligands for the DAT. Some of the modified GBR analogs (e.g. 8, 10, (-)-49, or (-)-50) displayed substantially higher selectivity (4736- to 693-fold) for the dopamine (DA) versus the serotonin (5HT) reuptake site than the parent compounds. The bis(p-fluoro) substitution in the (diphenylmethoxy)ethyl fragment slightly increased the affinity of the ligands at the DA reuptake site but reduced their selectivity at this site (e.g. 9 and 8, 11 and 10, or 17 and 16, respectively). Congeners, such as the series of monosubstituted and symmetrically disubstituted piperazines and trans-2,5-dimethylpiperazines, which lack the (diphenylmethoxy)ethyl substituent lost the affinity for the DAT yet exhibited very high potency for binding to the sigma receptors (e.g.28). The chiral pyrrolidine derivatives of 1, (-)-49, and (+)-49, exhibited an enantioselectivity ratio of 181 and 146 for the inhibition of DA reuptake and binding to the DAT, respectively.

Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

“…The compounds 6 , 7 and 8 (Scheme 2) were prepared by nucleophilic substitution reactions between the intermediate 5-(2-chloroethoxy-)-10,11-dihydro-5 H -dibenzo[ a,d ]cycloheptene ( 4 ) and the appropriate substituted piperazines in yields of between 33 and 41 % 58. Compound 5 was prepared by nucleophilic substitution between the intermediate (2-chloroethoxy)diphenylmethane 3 and anhydrous piperazine (Scheme 2) in a yield of 53 % 59.…”

“…Intermediate compound 4 was formed by reaction between dibenzosuberol and 2-chloroethanol in a yield of 70 %. Similarly, compound 3 was formed by reaction of benzhydrol and 2-chloroethanol in a yield of 82 % 58. The substituted piperazine, 1-(3-phenylpropyl)piperazine, was formed by a nucleophilic substitution reaction between anhydrous piperazine and 1-bromo-3-phenylpropane in a yield of 23 %.…”

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

“…109 Synthetic studies have focused on substitutions on the piperazine ring to introduce chirality to GBR 12909 110 or replacing this functional group with various nitrogen-containing saturated heterocycles. [110][111][112][113] Notably, two pyrrolidine derivatives displayed >100-fold enantioselectivity for inhibition of dopamine uptake. Whereas, the expansion of the piperazine ring to a seven-membered ring resulted in a compound equipotent to GBR 12909, for inhibition of dopamine uptake, but selectivity over inhibition of serotonin uptake was a remarkable 4,700-fold.…”

“…Whereas, the expansion of the piperazine ring to a seven-membered ring resulted in a compound equipotent to GBR 12909, for inhibition of dopamine uptake, but selectivity over inhibition of serotonin uptake was a remarkable 4,700-fold. 110 Expansion of the piperidine analogue series has led to some potent DAT ligands that show some divergence from the structure-activity relationships derived from the piperazinyl GBR 12909 analogues. [112][113][114] In particular, the terminal N-benzyl-piperidine analogue is equipotent to GBR 12909, whereas the N-benzyl analogue of GBR 12909 is 17-fold less potent in inhibiting dopamine uptake than the parent drug.…”

“…32 In addition, the piperazine ring system has been replaced with diamino-alkyl chains. 110,[115][116][117] One of these analogs, in which the piperazine ring was broken into two N-methyl groups linked by an ethyl chain, demonstrated highly potent and selective binding at DAT (IC 50 ¼ 10 nM v. 1,500 at SERT and > 10,000 at NET). 115 Additional modifications of the terminal phenyl ring of both GBR 12909 and 12935 by replacement with various heterocycles resulted in numerous novel and potent dopamine uptake inhibitors.…”