JJC8-091

Last updated
JJC8-091
JJC8-091.svg
Clinical data
Drug class Atypical dopamine reuptake inhibitor
Identifiers
  • 1-[4-[2-[bis(4-fluorophenyl)methylsulfinyl]ethyl]piperazin-1-yl]propan-2-ol
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C22H28F2N2O2S
Molar mass 422.53 g·mol−1
3D model (JSmol)
  • CC(CN1CCN(CC1)CCS(=O)C(C2=CC=C(C=C2)F)C3=CC=C(C=C3)F)O
  • InChI=1S/C22H28F2N2O2S/c1-17(27)16-26-12-10-25(11-13-26)14-15-29(28)22(18-2-6-20(23)7-3-18)19-4-8-21(24)9-5-19/h2-9,17,22,27H,10-16H2,1H3
  • Key:PHGOEMMHIGVMIN-UHFFFAOYSA-N

JJC8-091 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. [1] [2] [3] [4] It is a lead compound for potential treatment of psychostimulant use disorder (PSUD) and is under development by Encepheal Therapeutics for use as a pharmaceutical drug. [5]

The affinity (Ki) of JJC8-091 for the dopamine transporter (DAT) is 230 to 289 nM. [5] [1] [6] [7] In another study however, its affinities for the monoamine transporters were 16.7 nM for the DAT, 17,800 nM for the norepinephrine transporter (NET) (1,066-fold lower than for the DAT), and 1,770 nM for the serotonin transporter (SERT) (106-fold lower than for the DAT). [2] It has substantially higher affinity for the DAT than modafinil (Ki = 2,600–8,160 nM). [2] [5] Besides the DAT, JJC8-091 is a sigma σ1 receptor ligand (Ki = 454–1,010 nM; 2.0–3.5-fold lower than for the DAT). [5] [6] [7] [8] It also has high affinity for the dopamine D2 and D3 receptors and lower affinity for the dopamine D4 receptor (Ki = 298 nM, 480 nM, and 3,820 nM, respectively). [7]

JJC8-091 results in a mild, slow-onset, long-duration increase in dopamine levels in the nucleus accumbens in animals. [1] [3] The increases in nucleus accumbens dopamine levels with JJC8-091 are blunted relative to those with cocaine and JJC8-088 (a cocaine-like DRI) but are greater than those of JJC8-016 (an atypical DRI). [4] JJC8-091 does not increase locomotor activity in animals, is not self-administered, and does not substitute for cocaine, suggesting very low addictive potential. [3] [4] [1] Additionally, it reduces cocaine and methamphetamine self-administration, decreases escalation of methamphetamine intake, and blocks cocaine-induced reinstatement of drug-seeking behaviors. [3] [1] [5] [4] Unlike analogues including JJC8-088, JJC8-089, and RDS03-94, JJC8-091 did not show pro-motivational effects in animals. [9] [10]

JJC8-091 was first described in the scientific literature by 2016. [7] It shows a favorable predicted drug-like profile in terms of metabolism and pharmacokinetics. [1] [7] However, JJC8-091, similarly to analogues like JJC8-016, has been found to exert hERG inhibition. [11] In any case, modafinil and novel analogues like JJC8-091 are of interest in the potential treatment of PSUD. [12] [1] [5]

See also

Related Research Articles

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

<span class="mw-page-title-main">(+)-CPCA</span> Stimulant drug

(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine lacks the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).

<span class="mw-page-title-main">RTI-83</span> Chemical compound

RTI-83 is a phenyltropane derivative which represents a rare example of an SDRI or serotonin-dopamine reuptake inhibitor, a drug which inhibits the reuptake of the neurotransmitters serotonin and dopamine, while having little or no effect on the reuptake of the related neurotransmitter noradrenaline. With a binding affinity (Ki) of 55 nM at DAT and 28.4 nM at SERT but only 4030 nM at NET, RTI-83 has reasonable selectivity for DAT/SERT over NET

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

<span class="mw-page-title-main">Flmodafinil</span> Wakefulness-promoting drug/Dopamine reuptake inhibitor

Flmodafinil, also known as bisfluoromodafinil and lauflumide, is a wakefulness-promoting agent related to modafinil which has been developed for treatment of a variety of different medical conditions. These include chronic fatigue syndrome, idiopathic hypersomnia, narcolepsy, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease. Aside its development as a potential pharmaceutical drug, flmodafinil is sold online and used non-medically as a nootropic.

<span class="mw-page-title-main">JHW-007</span> Atypical dopamine reuptake inhibitor

JHW-007 is a cocaine analogue and a high affinity atypical dopamine reuptake inhibitor that is being researched for the treatment of cocaine addiction. JHW-007 has been found to blunt the psychostimulant effects of cocaine and reduce self-administration in rodents. JHW-007 exposure has been shown to block the conditioned place preference effects of cocaine. JHW-007 may directly antagonize the autoregulatory dopamine D2 receptor, a hypothesis that was developed following the observation of JHW-007's ability to inhibit D2 receptor-mediated currents in the midbrain.

<span class="mw-page-title-main">Esmodafinil</span> Unmarketed enantiomer of modafinil

Esmodafinil (also known as (S)-modafinil or (+)-modafinil; developmental code name CRL-40983) is the enantiopure (S)-(+)-enantiomer of modafinil. Unlike armodafinil ((R)-(–)-modafinil), esmodafinil has never been marketed on its own.

<span class="mw-page-title-main">RDS03-94</span> Dopamine reuptake inhibitor related to modafinil being developed for stimulant use disorder

RDS03-94, or RDS3-094, is an atypical dopamine reuptake inhibitor that was derived from the wakefulness-promoting agent modafinil.

<span class="mw-page-title-main">JJC8-088</span> Cocaine-like dopamine reuptake inhibitor derived from modafinil

JJC8-088 is a dopamine reuptake inhibitor (DRI) that was derived from the wakefulness-promoting agent modafinil.

(<i>S</i>)-MK-26 An atypical dopamine reuptake inhibitor with pro-motivational effects related to modafinil

(S)-MK-26 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is closely related to two other modafinil analogues, (S,S)-CE-158 and (S)-CE-123.

<span class="mw-page-title-main">CE-158</span> Chemical compound

CE-158 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is often but not always referred to as the enantiopure enantiomer (S,S)-CE-158 instead.

<span class="mw-page-title-main">JJC8-016</span> Abandoned drug

JJC8-016 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It was an early lead in the development of novel modafinil analogues with improved properties for potential use in the treatment of psychostimulant use disorder (PSUD).

<span class="mw-page-title-main">JJC8-089</span> Dopamine reuptake inhibitor related to modafinil

JJC8-089 is a dopamine reuptake inhibitor (DRI) that was derived from modafinil and is related to JJC8-016, JJC8-088, and JJC8-091. Its affinity (Ki) for the dopamine transporter (DAT) is 37.8 nM, for the norepinephrine transporter (NET) is 11,820 nM, for the serotonin transporter (SERT) is 6,800 nM, and for the sigma σ1 receptor is 2.24 nM. It also has significant affinity for several dopamine receptors. JJC8-089 has substantially higher affinity for the DAT than modafinil. The drug shows pro-motivational effects in animals. It was first described in the scientific literature by 2016.

References

  1. 1 2 3 4 5 6 7 Jordan CJ, Cao J, Newman AH, Xi ZX (November 2019). "Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine". Neuropharmacology. 158: 107609. doi:10.1016/j.neuropharm.2019.04.015. PMC   6745247 . PMID   31009632.
  2. 1 2 3 Aggarwal S, Mortensen OV (2023). "Discovery and Development of Monoamine Transporter Ligands". Drug Development in Psychiatry. Advances in Neurobiology. Vol. 30. pp. 101–129. doi:10.1007/978-3-031-21054-9_4. ISBN   978-3-031-21053-2. PMC   10074400 . PMID   36928847.{{cite book}}: |journal= ignored (help)
  3. 1 2 3 4 Hersey M, Bartole MK, Jones CS, Newman AH, Tanda G (July 2023). "Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors". Molecules. 28 (13): 5270. doi: 10.3390/molecules28135270 . PMC   10343811 . PMID   37446929.
  4. 1 2 3 4 Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH (February 2021). "Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder". Curr Opin Pharmacol. 56: 13–21. doi:10.1016/j.coph.2020.07.007. PMC   8247144 . PMID   32927246.
  5. 1 2 3 4 5 6 Newman AH, Ku T, Jordan CJ, Bonifazi A, Xi ZX (January 2021). "New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders". Annu Rev Pharmacol Toxicol. 61: 609–628. doi:10.1146/annurev-pharmtox-030220-124205. PMC   9341034 . PMID   33411583.
  6. 1 2 Giancola JB, Bonifazi A, Cao J, Ku T, Haraczy AJ, Lam J, Rais R, Coggiano MA, Tanda G, Newman AH (December 2020). "Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability". Eur J Med Chem. 208: 112674. doi:10.1016/j.ejmech.2020.112674. PMC   7680422 . PMID   32947229.
  7. 1 2 3 4 5 Cao J, Slack RD, Bakare OM, Burzynski C, Rais R, Slusher BS, Kopajtic T, Bonifazi A, Ellenberger MP, Yano H, He Y, Bi GH, Xi ZX, Loland CJ, Newman AH (December 2016). "Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors". J Med Chem. 59 (23): 10676–10691. doi:10.1021/acs.jmedchem.6b01373. PMC   5161041 . PMID   27933960.
  8. ↑ Hersey M, Mereu M, Jones CS, Bartole MK, Chen AY, Cao J, Hiranita T, Chun LE, Lopez JP, Katz JL, Newman AH, Tanda G (May 2024). "Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats". Eur J Neurosci. 59 (10): 2436–2449. doi:10.1111/ejn.16293. PMC  11108740. PMID   38444104.
  9. ↑ Meka, Nicolette M. "Assessment of Effort-related Motivational Effects of Novel Modafinil Analogs from NIDA Laboratories". ProQuest. Retrieved 22 September 2024.
  10. ↑ Ecevitoglu A, Meka N, Rotolo RA, Edelstein GA, Srinath S, Beard KR, Carratala-Ros C, Presby RE, Cao J, Okorom A, Newman AH, Correa M, Salamone JD (July 2024). "Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors". Neuropsychopharmacology. 49 (8): 1309–1317. doi:10.1038/s41386-024-01826-1. PMC  11224370. PMID   38429498.
  11. ↑ Ku TC, Cao J, Won SJ, Guo J, Camacho-Hernandez GA, Okorom AV, Salomon KW, Lee KH, Loland CJ, Duff HJ, Shi L, Newman AH (February 2024). "Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity". ACS Pharmacol Transl Sci. 7 (2): 515–532. doi:10.1021/acsptsci.3c00322. PMC  10863442. PMID   38357284.
  12. ↑ Hersey M, Bacon AK, Bailey LG, Coggiano MA, Newman AH, Leggio L, Tanda G (2021). "Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?". Front Neurosci. 15: 656475. doi: 10.3389/fnins.2021.656475 . PMC   8187604 . PMID   34121988.
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