MRZ-9547

MRZ-9547
Clinical data
Other names	(R)-Phenylpiracetam; (R)-Phenotropil; (R)-Fenotropil; (R)-Fonturacetam; Arfonturacetam; N-Carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone
Drug class	Atypical dopamine reuptake inhibitor; Pro-motivational agent
Identifiers
	IUPAC name 2-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]acetamide;
CAS Number	949925-07-9;
PubChem CID	781883;
ChemSpider	683574;
UNII	X4X99EKB3S;
Chemical and physical data
Formula	C12H14N2O2
Molar mass	218.256 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1[C@@H](CN(C1=O)CC(=O)N)C2=CC=CC=C2;
	InChI InChI=1S/C12H14N2O2/c13-11(15)8-14-7-10(6-12(14)16)9-4-2-1-3-5-9/h1-5,10H,6-8H2,(H2,13,15)/t10-/m0/s1; Key:LYONXVJRBWWGQO-JTQLQIEISA-N;

MRZ-9547, also known as (R)-phenylpiracetam, (R)-phenotropil, or (R)-fonturacetam, is a selective dopamine reuptake inhibitor (IC₅₀Tooltip half-maximal inhibitory concentration = 14.5 μM) that was developed by Merz Pharma.^[1]^[2]^[3]^[4]^[5]^[6] It is the (R)-enantiomer of the racetam and nootropic phenylpiracetam (phenotropil; fonturacetam).^[4]^[5]^[7]

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The drug was under development for the treatment of fatigue associated with Parkinson's disease and was in phase 1 clinical trials for this indication in June 2014.^[1] However, no recent development has been reported as of November 2017.^[1] There was also interest in MRZ-9547 for treatment of fatigue in people with depression and other conditions, but this was not pursued.^[2]^[5]

Similarly to other dopamine reuptake inhibitors and related agents, MRZ-9547 has been found to have pro-motivational effects in animals and to reverse motivational deficits induced by the dopamine depleting agent tetrabenazine.^[8]^[3]^[5]

The drug, as the enantiopure (R)-enantiomer of phenylpiracetam, was first described in the scientific literature by 2014.^[5]^[9]

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[1]
"MRZ 9547". AdisInsight. 4 November 2017. Retrieved 11 August 2024.
[2]
Stutz PV, Golani LK, Witkin JM (February 2019). "Animal models of fatigue in major depressive disorder". Physiology & Behavior. 199: 300–305. doi:10.1016/j.physbeh.2018.11.042. PMID 30513290. In a study performed by Sommer et al. (2014), healthy rats treated with the selective dopamine transport (DAT) inhibitor MRZ-9547 (Fig. 1) chose high effort, high reward more often than their untreated matched controls. Unlike similar studies, however, depressive symptoms were not induced before treatment; rather, baseline healthy controls were compared to healthy rats treated with MRZ-9547. [...] In one study, the selective DAT inhibitor MRZ-9547 increased the number of lever presses more than untreated controls (Sommer et al., 2014). The investigators concluded that such effort-based "decision making in rodents could provide an animal model for motivational dysfunctions related to effort expenditure such as fatigue, e.g. in Parkinson's disease or major depression." Based upon the findings with MRZ-9547, they suggested that this drug mechanism might be a valuable therapeutic entity for fatigue in neurological and neuropsychiatric disorders. [...] A high effort bias been reported with bupropion (Randall et al., 2015), lisdexamfetamine (Yohn etal., 2016e), and the DA uptake blockers MRZ-9547 (Sommer et al., 2014), PRX-14040 (Fig. 1) (Yohn et al., 2016d) and GBR12909 (Fig. 1) (Yohn et al., 2016c).
[3]
Salamone JD, Ecevitoglu A, Carratala-Ros C, Presby RE, Edelstein GA, Fleeher R, et al. (May 2022). "Complexities and paradoxes in understanding the role of dopamine in incentive motivation and instrumental action: Exertion of effort vs. anhedonia". Brain Research Bulletin. 182: 57–66. doi:10.1016/j.brainresbull.2022.01.019. hdl:10234/200412. PMID 35151797. Administration of TBZ reduces extracellular DA and DA D1 and D2 receptor signaling at doses that induce a low effort bias (Nunes et al. 2013). The effort-related effects of TBZ are reversible with DA agonists or drugs that block DA transport (DAT) and elevate extracellular levels of DA (Nunes et al. 2013a; Randall et al. 2014; Yohn et al. 2015a,b, 2016a,b,d; Salamone et al. 2016; Rotolo et al. 2019, 2020, 2021; Carratala-Ros et al., 2021b). Furthermore, DAT inhibitors such as lisdexamfetamine, PRX14040, MRZ-9547, GBR12909, (S)-CE-123, (S, S)-CE-158, CT 005404, as well as the catecholamine uptake inhibitor bupropion, increase selection of high-effort PROG lever pressing in rats tested on effort-based choice tasks (Sommer et al. 2014; Randall et al. 2015; Yohn et al. 2016a,b,d,e; Rotolo et al. 2019, 2020, 2021).
[4]
"1-Pyrrolidineacetamide, 2-oxo-4-phenyl-, (4R)-". PubChem. Retrieved 11 August 2024.
[5]
Sommer S, Danysz W, Russ H, Valastro B, Flik G, Hauber W (December 2014). "The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats". The International Journal of Neuropsychopharmacology. 17 (12): 2045–2056. doi:10.1017/S1461145714000996. PMID 24964269. Here, we tested the effects of MRZ-9547 [...], and its l-enantiomer MRZ-9546 on effort-related decision making in rats. The racemic form of these compounds referred to as phenotropil has been shown to stimulate motor activity in rats (Zvejniece et al., 2011) and enhance physical capacity and cognition in humans (Malykh and Sadaie, 2010). [...] MRZ-9547 turned out to be a DAT inhibitor as shown by displacement of binding of [125I] RTI-55 (IC50 = 4.82 ± 0.05 μM, n=3) to human recombinant DAT expressed in CHO-K1 cells and inhibition of DA uptake (IC50 = 14.5 ± 1.6 μM, n=2) in functional assays in the same cells. It inhibited norepinephrine transporter (NET) with an IC50 of 182 μM (one experiment in duplicate). The potencies for the l-enantiomer MRZ-9546 were as follows: DAT binding (Ki = 34.8 ± 14.8 μM, n=3), DAT function (IC50 = 65.5 ± 8.3 μM, n=2) and NET function (IC50 = 667 μM, one experiment performed in duplicate).
[6]
Dekundy A, Mela F, Hofmann M, Danysz W (June 2015). "Effects of dopamine uptake inhibitor MRZ-9547 in animal models of Parkinson's disease". Journal of Neural Transmission. 122 (6): 809–818. doi:10.1007/s00702-014-1326-8. PMID 25319446.
[7]
Veinberg G, Vavers E, Orlova N, Kuznecovs J, Domracheva I, Vorona M, et al. (2015). "Stereochemistry of phenylpiracetam and its methyl derivative: improvement of the pharmacological profile". Chemistry of Heterocyclic Compounds. 51 (7): 601–606. doi:10.1007/s10593-015-1747-9. ISSN 0009-3122. Phenylpiracetam was originally designed as a nootropic drug for the sustenance and improvement of the physical condition and cognition abilities of Soviet space crews.2 Later, especially during the last decade, phenylpiracetam was introduced into general clinical practice in Russia and in some Eastern European countries. The possible target receptors and mechanisms for the acute activity of this drug remained unclear, until very recently it was found that (R)-phenylpiracetam (5) (MRZ-9547) is a selective dopamine transporter inhibitor that moderately stimulates striatal dopamine release.19
[8]
Salamone JD, Correa M (2018). "Neurobiology and pharmacology of activational and effort-related aspects of motivation: rodent studies". Current Opinion in Behavioral Sciences. 22: 114–120. doi:10.1016/j.cobeha.2018.01.026. Several drugs that reverse the effects of tetrabenazine also can increase selection of high-effort PROG lever pressing when administered alone, including MSX-3 [27], and the DA transport blockers MRZ-9547 [26], bupropion [28], lisdexamfetamine [45], PRX-14040 [46], and GBR12909 [53].
[9]
WO application 2014005721, Russ H, Dekundy A, Danysz W, "Use of (r)-phenylpiracetam for the treatment of parkinson's disease", published 2014-01-09, assigned to Merz Pharma GmbH & Co. KGaA

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[AdisInsight-1] [1]
"MRZ 9547". AdisInsight. 4 November 2017. Retrieved 11 August 2024.

[StutzGolaniWitkin2019-2] [2]
Stutz PV, Golani LK, Witkin JM (February 2019). "Animal models of fatigue in major depressive disorder". Physiology & Behavior. 199: 300–305. doi:10.1016/j.physbeh.2018.11.042. PMID 30513290. In a study performed by Sommer et al. (2014), healthy rats treated with the selective dopamine transport (DAT) inhibitor MRZ-9547 (Fig. 1) chose high effort, high reward more often than their untreated matched controls. Unlike similar studies, however, depressive symptoms were not induced before treatment; rather, baseline healthy controls were compared to healthy rats treated with MRZ-9547. [...] In one study, the selective DAT inhibitor MRZ-9547 increased the number of lever presses more than untreated controls (Sommer et al., 2014). The investigators concluded that such effort-based "decision making in rodents could provide an animal model for motivational dysfunctions related to effort expenditure such as fatigue, e.g. in Parkinson's disease or major depression." Based upon the findings with MRZ-9547, they suggested that this drug mechanism might be a valuable therapeutic entity for fatigue in neurological and neuropsychiatric disorders. [...] A high effort bias been reported with bupropion (Randall et al., 2015), lisdexamfetamine (Yohn etal., 2016e), and the DA uptake blockers MRZ-9547 (Sommer et al., 2014), PRX-14040 (Fig. 1) (Yohn et al., 2016d) and GBR12909 (Fig. 1) (Yohn et al., 2016c).

[SalamoneEcevitogluCarratala-Ros2022-3] [3]
Salamone JD, Ecevitoglu A, Carratala-Ros C, Presby RE, Edelstein GA, Fleeher R, et al. (May 2022). "Complexities and paradoxes in understanding the role of dopamine in incentive motivation and instrumental action: Exertion of effort vs. anhedonia". Brain Research Bulletin. 182: 57–66. doi:10.1016/j.brainresbull.2022.01.019. hdl:10234/200412. PMID 35151797. Administration of TBZ reduces extracellular DA and DA D1 and D2 receptor signaling at doses that induce a low effort bias (Nunes et al. 2013). The effort-related effects of TBZ are reversible with DA agonists or drugs that block DA transport (DAT) and elevate extracellular levels of DA (Nunes et al. 2013a; Randall et al. 2014; Yohn et al. 2015a,b, 2016a,b,d; Salamone et al. 2016; Rotolo et al. 2019, 2020, 2021; Carratala-Ros et al., 2021b). Furthermore, DAT inhibitors such as lisdexamfetamine, PRX14040, MRZ-9547, GBR12909, (S)-CE-123, (S, S)-CE-158, CT 005404, as well as the catecholamine uptake inhibitor bupropion, increase selection of high-effort PROG lever pressing in rats tested on effort-based choice tasks (Sommer et al. 2014; Randall et al. 2015; Yohn et al. 2016a,b,d,e; Rotolo et al. 2019, 2020, 2021).

[PubChem-4] [4]
"1-Pyrrolidineacetamide, 2-oxo-4-phenyl-, (4R)-". PubChem. Retrieved 11 August 2024.

[SommerDanyszRuss2014-5] [5]
Sommer S, Danysz W, Russ H, Valastro B, Flik G, Hauber W (December 2014). "The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats". The International Journal of Neuropsychopharmacology. 17 (12): 2045–2056. doi:10.1017/S1461145714000996. PMID 24964269. Here, we tested the effects of MRZ-9547 [...], and its l-enantiomer MRZ-9546 on effort-related decision making in rats. The racemic form of these compounds referred to as phenotropil has been shown to stimulate motor activity in rats (Zvejniece et al., 2011) and enhance physical capacity and cognition in humans (Malykh and Sadaie, 2010). [...] MRZ-9547 turned out to be a DAT inhibitor as shown by displacement of binding of [125I] RTI-55 (IC50 = 4.82 ± 0.05 μM, n=3) to human recombinant DAT expressed in CHO-K1 cells and inhibition of DA uptake (IC50 = 14.5 ± 1.6 μM, n=2) in functional assays in the same cells. It inhibited norepinephrine transporter (NET) with an IC50 of 182 μM (one experiment in duplicate). The potencies for the l-enantiomer MRZ-9546 were as follows: DAT binding (Ki = 34.8 ± 14.8 μM, n=3), DAT function (IC50 = 65.5 ± 8.3 μM, n=2) and NET function (IC50 = 667 μM, one experiment performed in duplicate).

[DekundyMelaHofmann2015-6] [6]
Dekundy A, Mela F, Hofmann M, Danysz W (June 2015). "Effects of dopamine uptake inhibitor MRZ-9547 in animal models of Parkinson's disease". Journal of Neural Transmission. 122 (6): 809–818. doi:10.1007/s00702-014-1326-8. PMID 25319446.

[VeinbergVaversOrlova2015-7] [7]
Veinberg G, Vavers E, Orlova N, Kuznecovs J, Domracheva I, Vorona M, et al. (2015). "Stereochemistry of phenylpiracetam and its methyl derivative: improvement of the pharmacological profile". Chemistry of Heterocyclic Compounds. 51 (7): 601–606. doi:10.1007/s10593-015-1747-9. ISSN 0009-3122. Phenylpiracetam was originally designed as a nootropic drug for the sustenance and improvement of the physical condition and cognition abilities of Soviet space crews.2 Later, especially during the last decade, phenylpiracetam was introduced into general clinical practice in Russia and in some Eastern European countries. The possible target receptors and mechanisms for the acute activity of this drug remained unclear, until very recently it was found that (R)-phenylpiracetam (5) (MRZ-9547) is a selective dopamine transporter inhibitor that moderately stimulates striatal dopamine release.19

[SalamoneCorrea2018-8] [8]
Salamone JD, Correa M (2018). "Neurobiology and pharmacology of activational and effort-related aspects of motivation: rodent studies". Current Opinion in Behavioral Sciences. 22: 114–120. doi:10.1016/j.cobeha.2018.01.026. Several drugs that reverse the effects of tetrabenazine also can increase selection of high-effort PROG lever pressing when administered alone, including MSX-3 [27], and the DA transport blockers MRZ-9547 [26], bupropion [28], lisdexamfetamine [45], PRX-14040 [46], and GBR12909 [53].

[WO2014005721A1-9] [9]
WO application 2014005721, Russ H, Dekundy A, Danysz W, "Use of (r)-phenylpiracetam for the treatment of parkinson's disease", published 2014-01-09, assigned to Merz Pharma GmbH & Co. KGaA

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MRZ-9547

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