Identification of a GBR12935 homolog, LR1111, which is over 4,000-fold selective for the dopamine transporter, relative to serotonin and norepinephrine transporters
✍ Scribed by Richard B. Rothman; Bruce Lewis; Chris Dersch; Heng Xu; Lillian Radesca; Brian R. De Costa; Kenner C. Rice; Robert B. Kilburn; Hyacinth C. Akunne; Agu Pert
- Publisher
- John Wiley and Sons
- Year
- 1993
- Tongue
- English
- Weight
- 527 KB
- Volume
- 14
- Category
- Article
- ISSN
- 0887-4476
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✦ Synopsis
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 1 00-fold) inhibitors of ["Hldopamine reuptake, relative to [3H15-HT and [3H]norepinephrine uptake. The GBR12935 analog, 1-(2-(diphenylmethoxy)ethy1)-4-(3-phenylpropyl)homopiperazine
( L R l l l l ) , was synthesized as part of a systematic structure-activity study of analogs of GBR12935 and GBR12909. L R l l l l 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 L R l l l l a t 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. L R l l l 1 increased motoric activity in rats after intravenous administration. These indicate that LR1111 is a potent and highly selective inhibitor of the dopamine transporter.