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]
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| Other names | N-Methyl amisulpride; N′-Methylamisulpride; LB-102; LB102; LB-102-LAI |
| Drug class | Dopamine D2 and D3 receptor antagonist; Serotonin 5-HT2B and 5-HT7 receptor antagonist |
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| Formula | C18H29N3O4S |
| Molar mass | 383.51 g·mol−1 |
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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
edit- SEP-4199 (non-racemic amisulpride)
References
edit- ^ a b c d e "N-methyl amisulpride". AdisInsight. 26 December 2023. Retrieved 22 October 2024.
- ^ a b c d e f g Wu J, Kwan AT, Rhee TG, Ho R, d'Andrea G, Martinotti G, Teopiz KM, Ceban F, McIntyre RS (2023). "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. doi:10.1080/17512433.2023.2274538. PMID 37864424.
- ^ Biernat L, Grattan VT, Hixon MS, Prensky Z, Vaino AR (September 2022). "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. doi:10.1007/s00213-022-06185-7. PMID 35841422.
- ^ a b c Wong DF, Chand GB, Caito N, Eramo A, Grattan VT, Hixon MS, Nicol G, Lessie E, Prensky Z, Kuwabara H, Tian L, Valenta I, Schindler TH, Gründer G, Vaino AR (October 2024). "PET clinical study of novel antipsychotic LB-102 demonstrates unexpectedly prolonged dopamine receptor target engagement". Neuropsychopharmacology. doi:10.1038/s41386-024-01951-x. PMC 11632090. PMID 39414986.
- ^ a b Grattan V, Vaino AR, Prensky Z, Hixon MS (August 2019). "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. doi:10.1021/acsomega.9b02144. PMC 6714530. PMID 31497735.
- ^ Martinot JL, Paillère-Martinot ML, Poirier MF, Dao-Castellana MH, Loc'h C, Mazière B (March 1996). "In vivo characteristics of dopamine D2 receptor occupancy by amisulpride in schizophrenia". Psychopharmacology (Berl). 124 (1–2): 154–158. doi:10.1007/BF02245616. PMID 8935811.
- ^ Smith RC, Leucht S, Davis JM (February 2019). "Maximizing response to first-line antipsychotics in schizophrenia: a review focused on finding from meta-analysis". Psychopharmacology (Berl). 236 (2): 545–559. doi:10.1007/s00213-018-5133-z. PMID 30506237.
- ^ Bordet C, Garcia P, Salvo F, Touafchia A, Galinier M, Sommet A, Montastruc F (January 2023). "Antipsychotics and risk of QT prolongation: a pharmacovigilance study". Psychopharmacology (Berl). 240 (1): 199–202. doi:10.1007/s00213-022-06293-4. PMID 36515735.
- ^ a b Price, Lawrence H. (3 April 2023). "Data-based decisions about antipsychotics and QT prolongation". The Brown University Psychopharmacology Update. 34 (5). Wiley: 7–8. doi:10.1002/pu.31012. ISSN 1068-5308.