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Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties

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Abstract

Rationale

Serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitors (SNRIs) have been proposed to have a higher efficacy and/or faster onset of action than previously available antidepressants.

Objectives

We examined in biochemical, electrophysiological and behavioural assays the antidepressant properties of (S)-(−)-4-[(3-fluorophenoxy)-phenyl]methyl-piperidine (F-98214-TA), a compound that displays very high affinity for 5-HT and NE transporters.

Results

F-98214-TA potently inhibited the uptake of both 5-HT and NE into rat brain synaptosomes (IC50=1.9 and 11.2 nM, respectively) and decreased the electrical activity of dorsal raphe serotonergic neurones (ED50=530.3 μg/kg i.v.), an effect completely abolished by the 5-HT1A antagonist WAY100,635. In acute behavioural assays in mice, the orally administered compound potentiated the 5-hydroxy-tryptophan (5-HTP)-induced syndrome [minimal effective dose (MED)=10 mg/kg], antagonized the hypothermia induced by a high dose of apomorphine (ED50=2 mg/kg) and reduced the immobility in the tail suspension test (MED=10 mg/kg). Moreover, it also decreased the immobility in the forced swimming test in mice and rats (30 mg/kg, p.o.). Chronic administration of F-98214-TA (14 days, 30 mg kg−1 day−1, p.o.) attenuated the hyperactivity induced by olfactory bulbectomy in rats, confirming its antidepressant-like properties. Interestingly, the same dosage regimen significantly increased the social interaction time in rats, suggesting an additional potential anxiolytic activity. In most assays the compound was more potent than fluoxetine, venlafaxine and desipramine.

Conclusions

F-98214-TA is a novel SNRI that displays greater potency than other reference antidepressants in animal models predictive of antidepressant and anxiolytic activities.

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Acknowledgements

This study was in part supported by the Ministry of Science and Technology of Spain (PROFIT 2000–2003, BFI 01/0592 and 1FD 97/1597) and the Department of Industry, Commerce and Tourism of the Basque Country Government (INTEK 2000–2003). R. Pena was granted by the Ministry of Science and Technology of Spain (MIT fellowship). We thank Begoña González, Gaizka Akarregi, Iñaki Marcos, Lourdes Lanza and Ma. Josefa Castillo for technical assistance.

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  1. José Angel Ruiz-Ortega

    Present address: Department of Pharmacology, University of the Basque Country, Leioa, 48940, Spain

Authors and Affiliations

  1. Department of Research, FAES FARMA, S. A., Máximo Aguirre 14, Leioa, 48940, Vizcaya, Spain

    Inés Artaiz, Arturo Zazpe, Ana Innerárity, Elena del Olmo, Ruth Pena, Luis Labeaga & Aurelio Orjales

  2. Department of Physiology and Pharmacology, University of Cantabria, Avda. de los Castros s/n, Santander, Cantabria, 39005, Spain

    Alvaro Díaz, José Angel Ruiz-Ortega, Elena Castro, Ruth Pena & Angel Pazos

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  1. Inés Artaiz
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Artaiz, I., Zazpe, A., Innerárity, A. et al. Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties. Psychopharmacology 182, 400–413 (2005). https://doi.org/10.1007/s00213-005-0087-3

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