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| Other names | LU-35138; LU35138 |
| Routes of administration | Unspecified |
| Drug class | Dopamine D4 receptor antagonist; Serotonin reuptake inhibitor |
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| Chemical and physical data | |
| Formula | C25H26ClN3O |
| Molar mass | 419.95 g·mol−1 |
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Lu 35-138 is a dual dopamine D4 receptor antagonist and serotonin reuptake inhibitor (SRI), among other actions, which was under development for the treatment of schizophrenia but was never marketed.[2][3][4][5] Its route of administration is unspecified.
The drug shows high affinity for the dopamine D4 receptor (Ki = 5 nM) and is a competitive antagonist of this receptor (Kb = 8 nM).[5] In addition, it is a potent serotonin reuptake inhibitor, with an IC50Tooltip half-maximal inhibitory concentration of 3.2 nM.[5] Subsequent research found that Lu 35-138 is a potent negative allosteric modulator or allosteric inhibitor of the serotonin transporter (SERT), with an IC50 of 43.8 nM in the later study.[6] Lu 35-138 also shows affinity for the α1-adrenergic receptor (Ki = 45 nM).[5] Its affinities for various other monoamine receptors have been reported as well, for instance at the dopamine D2 receptor (Ki = 72 nM; 14.4-fold lower than for the dopamine D4 receptor) and serotonin 5-HT2A receptor (Ki = 260 nM), with significant dopamine D2 receptor occupancy notably observed in vivo in rodents.[5] In addition to its actions at monoaminergic targets, Lu 35-138 is a hERG blocker, with an IC50 of 270 nM.[7] For comparison, haloperidol and sertindole had IC50 values for this action of 170 nM and 64 nM, respectively.[7]
Similarly to many antidepressants, Lu 35-138 produces antiaggressive effects acutely and proaggressive effects with chronic administration in rodents.[4] It reverses the hyperlocomotion induced by dextroamphetamine and phencyclidine (PCP) in rodents.[5] However, it was unable to affect the hyperlocomotion induced by a high dose of dextroamphetamine, which was said to reflect a preferential action on limbic versus striatal structures.[5] The drug also reduced dextroamphetamine-induced disruption of prepulse inhibition.[5] Continuous administration of Lu 35-138 reduced the number of spontaneously active dopaminergic neurons in the ventral tegmental area (VTA), which was said to be consistent with antipsychotic-like activity.[5] Lu 35-138 did not produce catalepsy in rodents or dystonia in monkeys, suggesting low risk of extrapyramidal symptoms (EPS).[5] Due to unfavorable physicochemical properties, the drug has been found to have very low oral bioavailability of less than 5% in rats.[8]
Lu 35-138 was first described in the scientific literature by 2002.[4] It was under development by Lundbeck in Denmark.[2] The drug reached phase 2 clinical trials for schizophrenia prior to the discontinuation of its development in December 2003.
See also
[edit]References
[edit]- 1 2 "Delving into the Latest Updates on LU-35138 with Synapse". Synapse. 23 May 2026. Retrieved 6 July 2026.
- ↑ Rotella, David P. (2 November 2012). "Monoaminergic Approaches for Treatment of Schizophrenia". Drug Discovery for Psychiatric Disorders. The Royal Society of Chemistry. p. 35–55. doi:10.1039/9781849734943-00035. ISBN 978-1-84973-365-6. Retrieved 6 July 2026.
Researchers at Lundbeck reported the discovery of LU 35-138 (41),61 a compound that has good D4 affinity (Ki 5 nM) and functions as a full antagonist combined with similarly potent serotonin receptor uptake inhibition (IC50 3 nM). This molecule retains some a1 and D2 receptor activity (ca. 10–15 greater than D4) and displays improved serotinergic receptor selectivity compared to clozapine, haloperidol, olanzapine and risperidone. In hyperlocomotion assays, 41 had ED50s of 4 mg/kg sc in rats (amphetamine-induced) and 13 mg/kg sc in mice (PCP-induced). LU 35-138 did not cause catalepsy in rats, did not degrade spatial memory in a water maze assay in rats and did not result in dystonia in primates. This profile suggested the potential for antipsychotic activity without negative extra-pyramidal or cognitive side-effects.
- 1 2 3 Mitchell, P.J.; Hogg, S. (2002). "Pre-clinical characterisation of Lu 35-138, a dopamine D4 receptor antagonist & serotonin reuptake inhibitor, in the resident-intruder model of antidepressant drug activity". European Neuropsychopharmacology. 12: 185. doi:10.1016/S0924-977X(02)80159-6. Retrieved 6 July 2026.
- 1 2 3 4 5 6 7 8 9 10 Hertel P, Didriksen M, Pouzet B, Brennum LT, Søby KK, Larsen AK, Christoffersen CT, Ramirez T, Marcus MM, Svensson TH, Di Matteo V, Esposito E, Bang-Andersen B, Arnt J (November 2007). "Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole), a dopamine D4 receptor antagonist and serotonin reuptake inhibitor: characterisation of its in vitro profile and pre-clinical antipsychotic potential". Eur J Pharmacol. 573 (1–3): 148–160. doi:10.1016/j.ejphar.2007.06.052. PMID 17689529.
- ↑ Salomon K, Abramyan AM, Plenge P, Wang L, Bundgaard C, Bang-Andersen B, Loland CJ, Shi L (October 2023). "Dynamic extracellular vestibule of human SERT: Unveiling druggable potential with high-affinity allosteric inhibitors". Proc Natl Acad Sci U S A. 120 (41): e2304089120. doi:10.1073/pnas.2304089120. PMC 10576121. PMID 37792512.
{{cite journal}}: CS1 maint: article number as page number (link) - 1 2 Graff C, Matz J, Christensen EB, Andersen MP, Kanters JK, Toft E, Pehrson S, Hardahl TB, Nielsen J, Struijk JJ (November 2009). "Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138". J Clin Pharmacol. 49 (11): 1331–1342. doi:10.1177/0091270009344853. PMID 19843657.
- ↑ Holm R, Andresen L, Strange C (May 2011). "Oral bioavailability of a poorly aqueous drug from three different SBE7-β-cyclodextrin based formulations in beagle dogs". Results Pharma Sci. 1 (1): 57–59. doi:10.1016/j.rinphs.2011.09.001. PMC 4150629. PMID 25755982.
Therefore, as expected with these physical chemical properties, the bioavailability of Lu 35-138 has been demonstrated to be less than 5% in rats when dosed as a suspension (data not shown).