ENX-104

ENX-104
Clinical data
Other namesENX104; Deuterated nemonapride enantiomer[1]
Routes of
administration		Oral[2]
Drug classDopamine D2 and D3 autoreceptor antagonist
Identifiers
  • 5-chloro-N-[(2S,3S)-1-[dideuterio(phenyl)methyl]-2-methylpyrrolidin-3-yl]-2-methoxy-4-(trideuteriomethylamino)benzamide
PubChem CID
Chemical and physical data
FormulaC21H21ClD5N3O2
Molar mass392.94 g·mol−1
3D model (JSmol)
  • [2H]C([2H])([2H])NC1=CC(OC)=C(C(N[C@@H](CC2)[C@H](C)N2C([2H])([2H])C3=CC=CC=C3)=O)C=C1Cl
  • InChI=InChI=1S/C21H26ClN3O2/c1-14-18(9-10-25(14)13-15-7-5-4-6-8-15)24-21(26)16-11-17(22)19(23-2)12-20(16)27-3/h4-8,11-12,14,18,23H,9-10,13H2,1-3H3,(H,24,26)/t14-,18-/m0/s1/i2D3,13D2
  • Key:KRVOJOCLBAAKSJ-KBBDZWSESA-N

ENX-104, also known as deuterated nemonapride enantiomer,[1] is a selective dopamine D2 and D3 receptor antagonist which is under development for the treatment of major depressive disorder.[2][3][4][5][6] It is specifically under development for the treatment of major depressive disorder characterized by anhedonia.[4][2] The drug is being developed for use at low doses to preferentially block presynaptic dopamine D2 and D3 autoreceptors and hence to enhance rather than inhibit dopaminergic neurotransmission.[2][4][7][5][6] It is taken by mouth.[2]

Pharmacology

Pharmacodynamics

ENX-104 is intended for use at low doses to produce preferential presynaptic dopamine D2 and D3 autoreceptor antagonism and consequent enhancement of dopaminergic neurotransmission.[2][4][7][5][6] The target occupancy of the dopamine D2 and D3 receptors is approximately 40 to 70%.[5][6] For comparison, dopamine D2 receptor occupancy of 65 to 80% is associated with antipsychotic-like effects and hence with substantial postsynaptic dopamine D2 receptor antagonism in animals.[8][9] ENX-104 has been found to increase dopamine and serotonin levels in the nucleus accumbens and prefrontal cortex.[6] It was also found to augment amphetamine-induced dopamine release.[6] In accordance with these findings, the drug was found to produce anti-anhedonia-like effects, specifically increased reward responsiveness, in animals.[5] Low doses of amisulpride likewise showed anti-anhedonia-like effects.[5]

ENX-104 is not expected to induce motor side effects like extrapyramidal symptoms (EPS) or catalepsy at the low doses employed, as these effects require higher occupancy of the D2 receptor (e.g., ~80%).[5]

ENX-104 is highly potent as a dopamine receptor antagonist.[5] Its affinities are 0.01 nM for the dopamine D2L receptor, 0.1 nM for the dopamine D2S receptor, 0.2 nM for the dopamine D3 receptor (2- to 20-fold lower than for the D2 receptor), and 1.6 nM for the dopamine D4 receptor (8- to 160-fold lower than for the D2 receptor).[5][6] The drug is also a weak partial agonist or antagonist of the serotonin 5-HT2A receptor, with an EC50Tooltip half-maximal effective concentration of 14 nM (70- to 1,400-fold lower than its affinity for the D2 receptor) and an Emax of approximately 40%.[5] Conversely, ENX-104 showed little or no functional activity at the serotonin 5-HT1A or 5-HT7 receptor.[5]

Chemistry

ENX-104 is a benzamide derivative.[2][10] It is a partially-deuterated analog of the drug nemonapride, which is used to treat schizophrenia.[11][12][1]

Clinical trials

As of September 2024, ENX-104 is in phase 1 clinical trials for major depressive disorder.[2][4][7] It is under development by Engrail Therapeutics.[2][4]

See also

References

  1. ^ a b c "Engrail Therapeutics Corporate-Summary: 1Q 24" (PDF). Retrieved 2024-10-24.
  2. ^ a b c d e f g h i "ENX 104". AdisInsight. 27 September 2024. Retrieved 22 October 2024.
  3. ^ "Delving into the Latest Updates on ENX-104 with Synapse". Synapse. 13 October 2024. Retrieved 22 October 2024.
  4. ^ a b c d e f "Engrail Therapeutics Initiates ENX-104 Clinical Program for the Treatment of Major Depressive Disorder Characterized by Anhedonia". markets.businessinsider.com. 18 September 2024. Retrieved 22 October 2024.
  5. ^ a b c d e f g h i j k Vadodaria K, Kangas BD, Garvey DS, Brubaker W, Pizzagalli DA, Sudarsan V, et al. (December 2022). "ACNP 61st Annual Meeting: Poster Abstracts P271-P540: P351. Anti-Anhedonic Profile of ENX-104, a Novel and Highly Potent Dopamine D2/3 Receptor Antagonist". Neuropsychopharmacology. 47 (Suppl 1): 220–370 (265–266). doi:10.1038/s41386-022-01485-0. PMC 9714399. PMID 36456694.
  6. ^ a b c d e f g Vadodaria K, Serrats J, Brubaker W, Sudarsan V, Vanover K (December 2023). "ACNP 62nd Annual Meeting: Poster Abstracts P251 - P500: P356. ENX-104, a Novel and Potent D2/3 Receptor Antagonist, Increased Extracellular Levels of Dopamine and Serotonin in the Nucleus Accumbens and Prefrontal Cortex of Freely-Moving Rats". Neuropsychopharmacology. 48 (Suppl 1): 211–354 (271–272). doi:10.1038/s41386-023-01756-4. PMC 10729596. PMID 38040810.
  7. ^ a b c Engrail Therapeutics (18 September 2024). "Engrail Therapeutics Initiates ENX-104 Clinical Program for the Treatment of Major Depressive Disorder Characterized by Anhedonia". GlobeNewswire News Room (Press release). Retrieved 22 October 2024.
  8. ^ Wadenberg ML (January 2010). "Conditioned avoidance response in the development of new antipsychotics". Curr Pharm Des. 16 (3): 358–370. doi:10.2174/138161210790170085. PMID 20109144.
  9. ^ Wadenberg ML, Hicks PB (1999). "The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics?". Neurosci Biobehav Rev. 23 (6): 851–862. doi:10.1016/s0149-7634(99)00037-8. PMID 10541060.
  10. ^ "ENX-104 boosts dopamine and serotonin in rat brain". BioWorld. Clarivate.
  11. ^ WO 2023130119, Vadodaria K, Vanover K, Serrats J, Sudarsan V, Garvey D, "Preparation of deuterated pyrrolidin derivatives as modulators of dopamine and serotonin neurotransmission useful in treatment of diseases", assigned to Engrail Therapeutics, Inc. 
  12. ^ Shun-ichiro U, Yusuke S, Shogo M, Naoki K, Yoshiharu I (2017). "Concise, Protecting-Group-Free Synthesis of (+)-Nemonapride via Eu(OTf)3-Catalyzed Aminolysis of 3,4-Epoxy Alcohol". Chemical & Pharmaceutical Bulletin. 65 (1). Pharmaceutical Society of Japan: 22–24. doi:10.1248/cpb.c16-00568. ISSN 0009-2363. PMID 28049911.