Identification of a GBR12935 homolog, LR1111, which is over 4,000‐fold selective for the dopamine transporter, relative to serotonin and norepinephrine transporters

Abstract

The di-substituted piperazines, GBR12909 (1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-[3- phenylpropyl]piperazine) and GBR12935 (1-[2-(diphenyl-methoxy)-ethyl]-4-(3-phenylpropyl)piperazine), are potent and selective (20-to 100-fold) inhibitors of [3H]dopamine reuptake, relative to [3H]5-HT and [3H]norepinephrine uptake. The GBR12935 analog, 1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)homopiperazine (LR1111), was synthesized as part of a systematic structure-activity study of analogs of GBR12935 and GBR12909. LR1111 differs from GBR12935 by the addition of a methylene group into the piperazine ring to yield a compound with a seven-member homopiperazine ring. The IC50 values for LR1111 at the dopamine, norepinephrine, and serotonin transporters were 7.2 nM, 34,072 nM, and greater than 20,000 nM, respectively, whereas the IC50 values of GBR12935 were 3.7 nM, 289 nM, and 1261 nM for these same transporters. This demonstrates that the addition of a single methylene group in the piperazine ring results in a compound with similar affinity but significantly higher selectivity for the dopamine transporter. LR1111 increased motoric activity in rats after intravenous administration. These indicate that LR1111 is a potent and highly selective inhibitor of the dopamine transporter.

(+)-Fenfluramine and Its Major Metabolite, (+)-Norfenfluramine, Are Potent Substrates for Norepinephrine Transporters

“…For the in vitro experiments, IC 50 and EC 50 values were determined using the nonlinear least-squares curve fitting program MLAB-PC (Civilized Software, Bethesda, MD) as described previously (Rothman et al, 1993). K i values were calculated from uptake assay results according to the following formula: (Cheng and Prusoff, 1973).…”

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

“…The effect of dFEN and mCPP on uptake of [ 3 H]5-HT and [ 3 H]DA was evaluated using published methods (Rothman et al 1993). Rats were euthanized with CO 2 and decapitated.…”

Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse

“…The effect of test agents on [ 3 H]DA and [ 3 H]5-HT reuptake was evaluated using published methods (Rothman et al, 1993). Briefly, synaptosomes were prepared from rat caudate for [ 3 H]DA reuptake, or from whole rat brain minus cerebellum for [ 3 H]5-HT reuptake.…”

“…As previously described (Rothman et al, 1993), IC50 values were determined using the nonlinear leastsquares curve-fitting program MLAB-PC (Civilized Software, Bethesda, MD). In reuptake experiments, Ki values were calculated according to the formula: Ki ϭ IC50/(1ϩL/Km) where L is the concentration of the radiolabeled drug ( (Hyttel and Larsen, 1985), indatraline has high affinity at all three transporters.…”