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Lu AF35700

Lu AF35700
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
  • 4-[(1R,3S)-6-chloro-3-(2,3,4,5,6-pentadeuteriophenyl)-2,3-dihydro-1H-inden-1-yl]-2,2-dimethyl-1-(trideuteriomethyl)piperazine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC22H27ClN2
Molar mass354.92 g·mol−1
3D model (JSmol)
  • [2H]C1=C(C(=C(C(=C1[2H])[2H])[C@@H]2C[C@H](C3=C2C=CC(=C3)Cl)N4CCN(C(C4)(C)C)C([2H])([2H])[2H])[2H])[2H]
  • InChI=1S/C22H27ClN2/c1-22(2)15-25(12-11-24(22)3)21-14-19(16-7-5-4-6-8-16)18-10-9-17(23)13-20(18)21/h4-10,13,19,21H,11-12,14-15H2,1-3H3/t19-,21+/m0/s1/i3D3,4D,5D,6D,7D,8D
  • Key:BYPMJBXPNZMNQD-WHCYFCLHSA-N

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. ^ a b c d e f g Kane JM, Kinon BJ, Forray C, Such P, Mittoux A, Lemming OM, et al. (October 2022). "Efficacy and safety of Lu AF35700 in treatment-resistant schizophrenia: A randomized, active-controlled trial with open-label extension". Schizophrenia Research. 248: 271–278. doi:10.1016/j.schres.2022.09.012. PMID 36115192.
  2. ^ a b c d e "Lu AF35700". AdisInsight. 5 November 2023. Retrieved 30 May 2026.
  3. ^ a b c "Delving into the Latest Updates on Lu-AF-35700 with Synapse". Synapse. 9 May 2026. Retrieved 30 May 2026.
  4. ^ a b c d e f g h Ye N, Wang Q, Li Y, Zhen X (March 2025). "Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities". Medicinal Research Reviews. 45 (2): 755–787. doi:10.1002/med.22086. PMID 39300769.
  5. ^ a b c d e f Gjervig Jensen K, Tornby Christoffersen C, Graulund Hvenegaard M, Didriksen M, Jørgensen M (September 2022). "Distal kinetic deuterium isotope effect: Phenyl ring deuteration attenuates N-demethylation of Lu AF35700". Bioorganic & Medicinal Chemistry Letters. 72 128879. doi:10.1016/j.bmcl.2022.128879. PMID 35809818.
  6. ^ a b c d "NCT02717195-Prot" (PDF). cdn.clinicaltrials.gov.
  7. ^ a b Riga MS, Paz V, Didriksen M, Celada P, Artigas F (August 2023). "Lu AF35700 reverses the phencyclidine-induced disruption of thalamo-cortical activity by blocking dopamine D1 and D2 receptors". European Journal of Pharmacology. 953 175802. doi:10.1016/j.ejphar.2023.175802. PMID 37295763.

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