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Mesdopetam

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Mesdopetam
Clinical data
Other namesIRL-790; IRL790; IPN60170
Drug classAtypical dopamine D2 and D3 receptor antagonist
Pharmacokinetic data
Elimination half-life7 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
FormulaC12H18FNO3S
Molar mass275.34 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 (INNTooltip 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]

Pharmacology

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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

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

Clinical development

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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 INNTooltip 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

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References

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  1. ^ a b 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. ^ a b "Mesdopetam - Integrative Research Laboratories". AdisInsight. 6 September 2024. Retrieved 25 September 2024.
  3. ^ a b c d e f g h 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. ^ a b c 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. ^ a b 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. ^ a b c d e f g h i j 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. 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. ^ a b c 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 (March 2024). "Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis". Neurotherapeutics. 21 (2): e00334. doi:10.1016/j.neurot.2024.e00334. PMC 10937958. PMID 38368170. 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. ^ a b 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.
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