Vanoxerine dihydrochloride

Vanoxerine is an antagonist of dopamine transporter (DAT1) with Ki value of 16.9nM [1].

As an antagonist of DAT, vanoxerine is developed for treatment of Parkinson's disease and depression but has no effect on these diseases. Vanoxerine is also found to have desirable cardiac antiarrhythmic properties. It is a blocker of cardiac hERG (hKv11.1) with IC50 value of 0.84nM. It also blocks the ICa,L and hNav1.5 channel with IC50 values of 320nM and 830nM, respectively. Vanoxerine does not significantly prolong Purkinje fiber APD60 and APD90 and has no significant effect on QT or TDR. Further, the clinical trial demonstrates that the effective concentrations of vanoxerine are well tolerated and safe in man [2].

References:
[1] Giros B, el Mestikawy S, Godinot N, Zheng K, Han H, Yang-Feng T, Caron MG. Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. Mol Pharmacol. 1992 Sep;42(3):383-90.
[2] Lacerda AE, Kuryshev YA, Yan GX, Waldo AL, Brown AM. Vanoxerine: cellular mechanism of a new antiarrhythmic. J Cardiovasc Electrophysiol. 2010 Mar;21(3):301-10.

Pharmacological characterization of the discriminative-stimulus effects of GBR 12909.[Pubmed:1678014]

J Pharmacol Exp Ther. 1991 Aug;258(2):626-32.

Squirrel monkeys were trained to discriminate the selective dopamine uptake inhibitor GBR 12909 (1-[2-[bis(4-fluorophenyl)-methoxy] ethyl]-4-(3-phenylpropyl)piperazine) from saline in a two-lever drug-discrimination procedure. After i.v. injections of GBR 12909, 10 consecutive responses on one lever produced food, whereas after i.v. saline, 10 consecutive responses on the other lever produced food. By using a cumulative-dosing procedure, several inhibitors of monoamine uptake as well as dopamine receptor agonists and antagonists were evaluated for their ability to substitute for, or attenuate, the discriminative-stimulus effects of GBR 12909. Dopamine uptake inhibitors, including GBR 12909, cocaine, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane, mazindol, bupropion and methylphenidate, as well as the dopamine releasing drug (+)-amphetamine substituted fully (greater than 80% drug-lever responding) for the training dose of GBR 12909. In contrast, the selective norepinephrine uptake inhibitors, desipramine and talsupram, and the selective serotonin uptake inhibitor, citalopram, occasioned averages of only 13 to 19% drug-lever responding. The dopamine D1 agonist SKF 81297 (6-chloro-7,8-ddhydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3- benzazepine), the D2 agonists, (+)-4-propyl-9-hydroxynaphthoxazine and quinpirole, and the nonselective dopamine agonist, (-)-apomorphine, all occasioned a majority of responses (mean = 56-82%) on the drug-appropriate lever. The D1 partial agonists, R-SKF 38393 (R-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro- [1H]-3-benzazepine) and SKF 75670 (7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-[1H]-3-benzazepine), however, occasioned an average of no more than 21% drug-appropriate responding.(ABSTRACT TRUNCATED AT 250 WORDS)

GBR-12909 and fluspirilene potently inhibited binding of [3H] (+)3-PPP to sigma receptors in rat brain.[Pubmed:1980329]

Life Sci. 1990;47(22):PL133-7.

Fluspirilene and GBR-12909, two compounds structurally similar to BMY-14802 and haloperidol, were assessed for their ability to interact with sigma receptors. Fluspirilene, an antipsychotic agent that interacts potently with dopamine receptors, inhibited the binding of [3H]-(+) 3-PPP (IC50 = 380 nM) more potently than rimcazole, a putative sigma antagonist that was tested clinically for antipsychotic activity. GBR-12909, a potent dopamine uptake blocker, also inhibited the binding of [3H]-(+) 3-PPP with an IC50 of 48 nM. However, other compounds that block the re-uptake of catecholamines, such as nomifensine, desipramine, imipramine, xylamine, benztropine and cocaine, were much weaker than GBR-12909 as sigma ligands. Thus, GBR-12909 and fluspirilene, compounds structurally similar to BMY-14802, are potent sigma ligands.

The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action.[Pubmed:2530094]

Eur J Pharmacol. 1989 Aug 3;166(3):493-504.

The neurochemical profile of GBR 12909 (1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)pipera zine) was investigated. GBR 12909 was a potent and selective inhibitor of synaptosomal dopamine uptake (KI = 1 nM), with a 20-fold lower affinity for the histamine H1-receptor and a more than 100-fold affinity for the noradrenaline and 5-HT uptake carriers, the dopamine D-1, D-2, 5-HT2, 5-HT1A and alpha 1-receptors and voltage-dependent sodium channels. GBR 12909 (3 microM) was without effect on muscarinic, alpha 2, beta 1 + 2, gamma-aminobutyric acid (GABA) and benzodiazepine receptors, and on choline and GABA uptake carriers. The selective dopamine uptake inhibitory profile of GBR 12909 was confirmed by ex vivo uptake experiments. GBR 12909 inhibited uptake in vitro in a competitive manner as did cocaine and methylphenidate. [3H]GBR 12935 binding was competitively inhibited by GBR 12909 as well as by dopamine, cocaine and methylphenidate. Off-rate analysis of the [3H]GBR 12935 binding excluded the presence of allosteric binding sites on the dopamine carrier complex. Instead, the data favored the notion that GBR 12909 inhibits dopamine uptake by binding to the dopamine binding site on the carrier protein itself, thereby blocking the carrier process. In conclusion, GBR 12909 is a highly selective inhibitor of dopamine uptake, both in vivo and in vitro. At the moment GBR 12909 is the only compound with this neurochemical profile. The selective effect of GBR 12909 on this neuronal system makes it an interesting experimental tool and a potential antidepressant agent.

Behavioral properties of GBR 12909, GBR 13069 and GBR 13098: specific inhibitors of dopamine uptake.[Pubmed:6237922]

Eur J Pharmacol. 1984 Aug 17;103(3-4):241-8.

Two aryl 1,4-dialkylpiperazines (GBR 12909 and GBR 13098) and one aryl 1,4-dialkenylpiperazine (GBR 13069) were very potent inhibitors of [3H]dopamine uptake in vitro in tissue slices obtained from rat neostriatum (IC50 values between 40 and 51 nM). Each compound was considerably weaker as an inhibitor of [3H]norepinephrine uptake in tissue slices obtained from rat occipital cortex (IC50 values between 560 and 2600 nM). These compounds thus are relatively specific inhibitors of [3H]dopamine uptake in vitro. The three compounds caused ipsilateral circling in rats with unilateral lesions of the nigrostriatal pathway as well as increased locomotor activity in naive mice, both of which could be greatly attenuated by pretreatment of the rodents with the dopamine receptor antagonist haloperidol. It thus follows that the compounds have dopaminergic activity in vivo. Ex vivo experiments with GBR 13069 (drug administration in vivo, uptake in vitro) suggested that these compounds may have the same relative specificity as dopamine uptake blockers in vivo. These compounds should prove to be useful pharmacological agents.

Vanoxerine dihydrochloride (GBR-12909 dihydrochloride) is a competitive, potent, and highly selective dopamine reuptake inhibitor (Ki=1 nM). Vanoxerine dihydrochloride (GBR-12909 dihydrochloride) binds to the target site on the dopamine transporter (DAT).

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