Mesdopetam

Last updated
Mesdopetam
Mesdopetam.svg
Clinical data
Other namesIRL-790; IRL790; IPN60170
Drug class Atypical dopamine D2 and D3 receptor antagonist
Pharmacokinetic data
Elimination half-life 7 hours [1]
Identifiers
  • N-[2-(3-fluoro-5-methylsulfonylphenoxy)ethyl]propan-1-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C12H18FNO3S
Molar mass 275.34 g·mol−1
3D model (JSmol)
  • CCCNCCOC1=CC(=CC(=C1)S(=O)(=O)C)F
  • InChI=1S/C12H18FNO3S/c1-3-4-14-5-6-17-11-7-10(13)8-12(9-11)18(2,15)16/h7-9,14H,3-6H2,1-2H3
  • Key:OSBPYFBXSLJHCR-UHFFFAOYSA-N

Mesdopetam (INN Tooltip International Nonproprietary Name; developmental code names IRL-790, IPN60170) is a dopamine D2 and D3 receptor antagonist with preference for the D3 receptor which is under development for the treatment of Parkinson's disease, drug-induced dyskinesia, and psychotic disorders. [2] [3] [4] [5] [6] It has been described by its developers as having "psychomotor stabilizing" properties. [7] [8]

Contents

Pharmacology

The described intention behind mesdopetam was to develop a novel dopamine D2 and D3 receptor antagonist based on agonist- rather than antagonist-like structural motifs and with agonist-like physicochemical properties (e.g., smaller molecular size, greater hydrophilicity). [3] [9] [6] It was hypothesized that this would result in an antagonist with specific dopamine receptor interactions more similar to those of agonists like dopamine but without any intrinsic activity, in turn resulting in different in vivo effects than conventional dopamine receptor antagonists. [9] [6] Specifically, antidyskinetic and antipsychotic effects with fewer or no motor side effects was sought. [6] There is also extensive preclinical research to suggest that D3 receptor antagonists reduce levodopa-induced dyskinesia without compromising the antiparkinsonian effects of levodopa. [3]

Mesdopetam has 6- to 8-fold preference for the dopamine D3 receptor (Ki = 90 nM) over the dopamine D2 receptor (Ki = 540–750 nM). [4] [6] It displays a paradoxical agonist-like binding mode in spite of its lack of activational efficacy. [3] [9] [6] By antagonizing D3 autoreceptors, D3 receptor antagonists like mesdopetam have been found to disinhibit dopamine release in the prefrontal cortex, ventral tegmental area, and striatum, which might be involved in the possible therapeutic benefits of these agents. [4] [6] The drug is also a ligand of the sigma σ1 receptor (Ki = 870 nM) and has some affinity for certain serotonin receptors including the serotonin 5-HT1A and 5-HT2A receptors. [3] [6] In animals, mesdopetam has no effect on spontaneous locomotor activity at assessed doses but antagonizes levodopa-induced dyskinesia and reduces dextroamphetamine- and dizocilpine-induced locomotor hyperactivity. [6]

Side effects

Side effects of mesdopetam in clinical trials have been reported to include worsened parkinsonism, headache, fatigue, asthenia, and dissociation. [5] [1]

Clinical development

Mesdopetam was first described in the literature in 2012. [6] [10] As of September 2024, it is in phase 2/3 clinical trials for Parkinson's disease, phase 1 trials for drug-induced dyskinesia, and is in preclinical development for psychotic disorders (specifically Parkinson's disease psychosis). [2] [11] It is also of interest for potential treatment of impulse control disorders. [11] In 2019, mesdopetam received an INN Tooltip International Nonproprietary Name with a novel -"dopetam" suffix supposedly representing a new mechanism of action among dopamine receptor modulators. [12] In 2023, it was reported that mesdopetam failed to meet a primary anti-dyskinetic endpoint in a phase 2b trial. [3] However, indications of efficacy were still seen and a phase 3 trial is being planned. [3] No dopamine D3 receptor antagonists have yet completed development or been approved for the treatment of levodopa-induced dyskinesia. [3]

See also

Related Research Articles

<span class="mw-page-title-main">Amantadine</span> Medication used to treat dyskinesia

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It is also used for a variety of other uses. The drug is taken by mouth.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

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

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Ropinirole</span> Dopamine agonist medication

Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). It is taken by mouth.

<span class="mw-page-title-main">Pramipexole</span> Dopamine agonist medication

Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.

<span class="mw-page-title-main">Rotigotine</span> Dopamine agonist medication

Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal patch which provides a slow and constant supply of the drug over the course of 24 hours.

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

Dihydroergocryptine (DHEC), sold under the brand names Almirid and Cripar among others, is a dopamine agonist of the ergoline group that is used as an antiparkinson agent in the treatment of Parkinson's disease. It is taken by mouth.

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

Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinson's disease (PD) experiencing "off" episodes. Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa. An "off" episode is a time when a patient's medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.

<span class="mw-page-title-main">Levodopa</span> Dopaminergic medication

Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat.

<span class="mw-page-title-main">Pimavanserin</span> Atypical antipsychotic medication

Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist, but rather is a selective inverse agonist of the serotonin 5-HT2A receptor.

Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis.

<span class="mw-page-title-main">Pardoprunox</span> Antiparkinsonian compound researched for the treatment of depression and anxiety disorders

Pardoprunox (INN) is an antiparkinsonian drug developed by Solvay for the treatment of Parkinson's disease that reached phase III clinical trials before being discontinued. It was also being investigated for the treatment of depression and anxiety but these indications appear to have been abandoned as well.

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

Sarizotan (EMD-128,130) is a selective 5-HT1A receptor agonist and D2 receptor antagonist, which has antipsychotic effects, and has also shown efficacy in reducing dyskinesias resulting from long-term anti-Parkinsonian treatment with levodopa.

<span class="mw-page-title-main">BP-897</span> Chemical compound

BP-897 is a drug used in scientific research which acts as a potent selective dopamine D3 receptor partial agonist with an in vitro intrinsic activity of ~0.6 and ~70x greater affinity for D3 over D2 receptors and is suspected to have partial agonist or antagonist activity in vivo. It has mainly been used in the study of treatments for cocaine addiction. A study comparing BP-897 with the potent, antagonistic, and highly D3 selective SB-277,011-A found, "SB 277011-A (1–10 mg/kg) was able to block cue-induced reinstatement of nicotine-seeking, indicating that DRD3 selective antagonism may be an effective approach to prevent relapse for nicotine. In contrast, BP 897 did not block the cue-induced reinstatement of nicotine-seeking or nicotine-taking under the FR5 schedule."

<span class="mw-page-title-main">OSU-6162</span> Chemical compound

OSU-6162 (PNU-96391) is a compound which acts as a partial agonist at both dopamine D2 receptors and 5-HT2A receptors. It acts as a dopamine stabilizer in a similar manner to the closely related drug pridopidine, and has antipsychotic, anti-addictive and anti-Parkinsonian effects in animal studies. Both enantiomers show similar activity but with different ratios of effects, with the (S) enantiomer (–)-OSU-6162 that is more commonly used in research, having higher binding affinity to D2 but is a weaker partial agonist at 5-HT2A, while the (R) enantiomer (+)-OSU-6162 has higher efficacy at 5-HT2A but lower D2 affinity.

Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).

GSK-598809 is a selective dopamine D3 receptor antagonist that is or was under development for the treatment of substance-related disorders, smoking withdrawal, and eating disorders like binge eating disorder.

Pirepemat is a drug which is under development for the prevention of falls in people with Parkinson's disease and Parkinson's disease dementia. It has been referred to as a "nootrope".

References

  1. 1 2 Sjöberg F, Waters S, Löfberg B, Sonesson C, Waters N, Tedroff J (May 2021). "A first-in-human oral dose study of mesdopetam (IRL790) to assess its safety, tolerability, and pharmacokinetics in healthy male volunteers". Pharmacol Res Perspect. 9 (3): e00792. doi:10.1002/prp2.792. PMC   8137807 . PMID   34018344.
  2. 1 2 "Mesdopetam - Integrative Research Laboratories". AdisInsight. 6 September 2024. Retrieved 25 September 2024.
  3. 1 2 3 4 5 6 7 8 Alsalmi M, Al-Kassmy J, Kang W, Palayew M, Huot P (2024). "Levodopa-induced dyskinesia: do current clinical trials hold hope for future treatment?". Expert Opin Pharmacother. 25 (1): 1–3. doi: 10.1080/14656566.2023.2298345 . PMID   38116733.
  4. 1 2 3 Kiss B, Laszlovszky I, Krámos B, Visegrády A, Bobok A, Lévay G, Lendvai B, Román V (January 2021). "Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders". Biomolecules. 11 (1): 104. doi: 10.3390/biom11010104 . PMC   7830622 . PMID   33466844.
  5. 1 2 AlShimemeri S, Fox SH, Visanji NP (June 2020). "Emerging drugs for the treatment of L-DOPA-induced dyskinesia: an update". Expert Opin Emerg Drugs. 25 (2): 131–144. doi:10.1080/14728214.2020.1763954. PMID   32366130.
  6. 1 2 3 4 5 6 7 8 9 10 Waters S, Sonesson C, Svensson P, Tedroff J, Carta M, Ljung E, Gunnergren J, Edling M, Svanberg B, Fagerberg A, Kullingsjö J, Hjorth S, Waters N (July 2020). "Preclinical Pharmacology of [2-(3-Fluoro-5-Methanesulfonyl-phenoxy)Ethyl](Propyl)amine (IRL790), a Novel Dopamine Transmission Modulator for the Treatment of Motor and Psychiatric Complications in Parkinson Disease". J Pharmacol Exp Ther. 374 (1): 113–125. doi:10.1124/jpet.119.264226. hdl: 11584/423003 . PMID   32358046.
  7. ↑ Fabbrini A, Guerra A (2021). "Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia". J Exp Pharmacol. 13: 469–485. doi: 10.2147/JEP.S265282 . PMC   8092630 . PMID   33953618.
  8. ↑ Dragašević-Mišković N, Petrović I, Stanković I, Kostić VS (February 2019). "Chemical management of levodopa-induced dyskinesia in Parkinson's disease patients". Expert Opin Pharmacother. 20 (2): 219–230. doi:10.1080/14656566.2018.1543407. PMID   30411647.
  9. 1 2 3 {{cite journal | vauthors = Stan TL, Ronaghi A, Barrientos SA, Halje P, Censoni L, Garro-Martínez E, Nasretdinov A, Malinina E, Hjorth S, Svensson P, Waters S, Sahlholm K, Petersson P | title = Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis | journal = Neurotherapeutics | volume = 21 | issue = 2 | pages = e00334 | date = March 2024 | pmid = 38368170 | pmc = 10937958 | doi = 10.1016/j.neurot.2024.e00334 | url = | quote = Mesdopetam is a dopamine type-2-receptor antagonist with a strong preference for D3Rs and more agonist-like physicochemical properties than other D3R antagonists. An agonist like binding mode at D3Rs has been proposed to contribute to its in vivo pharmacological profile as well as the good tolerability in patients with PD [[14], [15], [16], [17]].}}
  10. ↑ "Novel modulators of cortical dopaminergic- and nmda-receptor-mediated glutamatergic neurotransmission". Google Patents. 17 April 2012. Retrieved 26 September 2024.
  11. 1 2 Dong-Chen X, Yong C, Yang X, Chen-Yu S, Li-Hua P (February 2023). "Signaling pathways in Parkinson's disease: molecular mechanisms and therapeutic interventions". Signal Transduct Target Ther. 8 (1): 73. doi:10.1038/s41392-023-01353-3. PMC   9944326 . PMID   36810524.
  12. ↑ "IRLAB's IRL790 is proposed a unique INN by WHO". News Powered by Cision. 26 September 2019. Retrieved 26 September 2024.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.