Chemistry:N-Methylamisulpride

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Short description: Experimental antipsychotic


N-Methylamisulpride
Clinical data
Other namesN-Methyl amisulpride; N′-Methylamisulpride; LB-102; LB102; LB-102-LAI
Drug classDopamine D2 and D3 receptor antagonist; Serotonin 5-HT2B and 5-HT7 receptor antagonist
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC18H29N3O4S
Molar mass383.51 g·mol−1
3D model (JSmol)

N-Methylamisulpride (developmental code name LB-102) is a dopamine D2 and D3 receptor antagonist and serotonin 5-HT2B and 5-HT7 receptor antagonist which is under development for the treatment of schizophrenia.[1][2][3][4][5] It is a benzamide derivative and is the N-methylated analogue of amisulpride.[1][2] The drug is being developed for use both orally and parenterally.[1]

Amisulpride exhibits low passive diffusion through the blood–brain barrier and this requires higher doses for central nervous system activity.[2] N-Methylamisulpride has enhanced lipophilicity and hence improved passive diffusion through biological membranes like the blood–brain barrier compared to amisulpride.[2] This in turn is expected to provide a higher ratio of brain to peripheral concentrations.[2] The drug otherwise has similar pharmacodynamics and pharmacokinetics relative to amisulpride.[2][5]

N-Methylamisulpride appears to have considerably greater clinical potency compared to amisulpride owing to its improved lipophilicity and blood–brain barrier permeability.[2] A dosage of 50 mg/day N-methylamisulpride has been found to achieve 60 to 80% occupancy of the dopamine D2 receptor, whereas 300 to 400 mg/day amisulpride achieved around 70% occupancy and doses of 630 to 910 mg/day amisulpride achieved 70 to 80% occupancy of the receptor.[4][6]

Amisulpride has been associated with QT prolongation.[7][8][9] Due to its greater ratio of brain to peripheral concentrations and much lower doses, N-methylamisulpride is expected to have reduced risk of QT prolongation in comparison.[9][4]

As of December 2023, N-methylamisulpride is in phase 2 clinical trials for schizophrenia.[1] It is being developed by LB Pharmaceuticals.[1]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "N-methyl amisulpride". 26 December 2023. https://adisinsight.springer.com/drugs/800056770. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "A narrative review of non-racemic amisulpride (SEP-4199) for treatment of depressive symptoms in bipolar disorder and LB-102 for treatment of schizophrenia". Expert Rev Clin Pharmacol 16 (11): 1085–1092. 2023. doi:10.1080/17512433.2023.2274538. PMID 37864424. 
  3. ↑ "A randomized, double-blind, placebo controlled, phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of LB-102, a selective dopamine D2/3/5-HT7 inhibitor". Psychopharmacology (Berl) 239 (9): 3009–3018. September 2022. doi:10.1007/s00213-022-06185-7. PMID 35841422. 
  4. ↑ 4.0 4.1 4.2 "PET clinical study of novel antipsychotic LB-102 demonstrates unexpectedly prolonged dopamine receptor target engagement". Neuropsychopharmacology 50 (2): 372–377. October 2024. doi:10.1038/s41386-024-01951-x. PMID 39414986. 
  5. ↑ 5.0 5.1 "Antipsychotic Benzamides Amisulpride and LB-102 Display Polypharmacy as Racemates, S Enantiomers Engage Receptors D2 and D3, while R Enantiomers Engage 5-HT7". ACS Omega 4 (9): 14151–14154. August 2019. doi:10.1021/acsomega.9b02144. PMID 31497735. 
  6. ↑ "In vivo characteristics of dopamine D2 receptor occupancy by amisulpride in schizophrenia". Psychopharmacology (Berl) 124 (1–2): 154–158. March 1996. doi:10.1007/BF02245616. PMID 8935811. 
  7. ↑ "Maximizing response to first-line antipsychotics in schizophrenia: a review focused on finding from meta-analysis". Psychopharmacology (Berl) 236 (2): 545–559. February 2019. doi:10.1007/s00213-018-5133-z. PMID 30506237. 
  8. ↑ "Antipsychotics and risk of QT prolongation: a pharmacovigilance study". Psychopharmacology (Berl) 240 (1): 199–202. January 2023. doi:10.1007/s00213-022-06293-4. PMID 36515735. 
  9. ↑ 9.0 9.1 Price, Lawrence H. (3 April 2023). "Data-based decisions about antipsychotics and QT prolongation". The Brown University Psychopharmacology Update (Wiley) 34 (5): 7–8. doi:10.1002/pu.31012. ISSN 1068-5308. 



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