Chemistry:Lu AF35700

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Lu AF35700
File:Lu AF35700.svg
Clinical data
Other namesLu-AF35700; Lu-AF-35700; Deuterated zicronapine; Deuzicronapine; d8-Zicronapine; Zicronapine-D8
Routes of
administration		Oral[1]
Drug classDopamine receptor antagonist; Serotonin receptor antagonist
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC22H27ClN2
Molar mass354.92 g·mol−1
3D model (JSmol)

Lu AF35700, also known as d8-zicronapine, is an experimental antipsychotic which was under development for the treatment of schizophrenia and schizoaffective disorder but was never marketed.[2][3][4][1] It is taken orally.[2]

The drug is a non-selective dopamine receptor antagonist, including of the dopamine D1, D2, D3, D4, and D5 receptors (Ki = 0.56 nM, 4.1 nM, 16 nM, 6.8 nM, and 0.37 nM, respectively).[4][5][1][6] In addition, it is an antagonist of the serotonin 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT6 receptors (Ki = 0.96 nM, 0.4 nM, 1.5 nM, and 0.59 nM, respectively).[4][5][1][6] The drug also shows affinity for and acts as an antagonist of various adrenergic receptors.[4][5][6] It is not an antagonist of the muscarinic acetylcholine receptors, but does show high affinity for the histamine H1 receptor (Ki = 4 nM).[5] Lu AF35700 is unusual among antipsychotics in that it shows marked and in fact preferential blockade of the dopamine D1-like receptors in addition to the dopamine D2-like receptors.[1][7][6] This has conferred it with unique preclinical pharmacological effects and potential therapeutic benefits.[4][7][1]

The drug is an octadeuterated isotopologue of zicronapine (Lu 31-130).[4][5] Lu AF36152 is the N-desmethyl active metabolite of Lu AF35700.[5]

Lu AF35700 was under development by Lundbeck A/S.[2][3] It reached phase 3 clinical trials for schizophrenia and phase 1 trials for schizoaffective disorder prior to the discontinuation of its development.[2][3][4] The development of the drug appears to have been stopped by 2019.[2] Although it demonstrated clinical antipsychotic effectiveness, the drug failed to differentiate itself from conventional antipsychotics like olanzapine and risperidone for treatment-resistant schizophrenia in phase 3 trials.[4][1]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Efficacy and safety of Lu AF35700 in treatment-resistant schizophrenia: A randomized, active-controlled trial with open-label extension". Schizophrenia Research 248: 271–278. October 2022. doi:10.1016/j.schres.2022.09.012. PMID 36115192. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Lu AF35700". 5 November 2023. https://adisinsight.springer.com/drugs/800040600. 
  3. ↑ 3.0 3.1 3.2 "Delving into the Latest Updates on Lu-AF-35700 with Synapse". 9 May 2026. https://synapse.patsnap.com/drug/0ceae74ce54644d8b4380c5f4fd09dfc. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities". Medicinal Research Reviews 45 (2): 755–787. March 2025. doi:10.1002/med.22086. PMID 39300769. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Distal kinetic deuterium isotope effect: Phenyl ring deuteration attenuates N-demethylation of Lu AF35700". Bioorganic & Medicinal Chemistry Letters 72. September 2022. doi:10.1016/j.bmcl.2022.128879. PMID 35809818. 
  6. ↑ 6.0 6.1 6.2 6.3 "NCT02717195-Prot". https://cdn.clinicaltrials.gov/large-docs/95/NCT02717195/Prot_000.pdf. 
  7. ↑ 7.0 7.1 "Lu AF35700 reverses the phencyclidine-induced disruption of thalamo-cortical activity by blocking dopamine D1 and D2 receptors". European Journal of Pharmacology 953. August 2023. doi:10.1016/j.ejphar.2023.175802. PMID 37295763. 



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