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Chemical Compound Review

Milnace     (1R,2R)-2-(aminomethyl)-N,N- diethyl-1...

Synonyms: Toledomin, Midalcipran, Milnacipran, Ixel, Milnacipranum, ...
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Disease relevance of F 2207


Psychiatry related information on F 2207


High impact information on F 2207


Chemical compound and disease context of F 2207


Biological context of F 2207

  • Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder [18].
  • Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 microM; 7, 13 +/- 2.1 microM; 8, 88 +/- 1.4 microM; 12, 10 +/- 1.2 microM) [19].
  • Some are influenced by chirality (e.g. the dealkylation of citalopram and fluoxetine), although information on this aspect of disposition is still lacking for other drugs existing as racemates (e.g. mirtazapine and tianeptine) and milnacipran, which is probably a mixture of 4 stereoisomers [20].
  • OBJECTIVES: To elucidate the functional interaction between the stress-induced alteration of synaptic plasticity and therapeutic effects, we examined the anxiolytic mechanism(s) of milnacipran, focusing on modulation of long-term potentiation (LTP) in the hippocampal CA1 field [21].
  • The interaction between midalcipran and neurotransmitter receptors and binding sites in the CNS was studied in the rat in comparison with imipramine and desipramine [22].

Anatomical context of F 2207


Associations of F 2207 with other chemical compounds


Gene context of F 2207

  • Of these analogs, (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) is 30-fold stronger than milnacipran as an NMDA-receptor antagonist with virtually no inhibitory effect on the neurotransmitter re-uptake [32].
  • Patients with lower baseline ACTH levels on day 0 displayed a better clinical outcome when taking the combination of milnacipran and pindolol as shown in the differences in MADRS on day 42 [33].
  • Effect of pindolol and milnacipran versus milnacipran and placebo on plasma prolactin and adrenocorticotrophic hormone in depressed subjects [33].
  • A series of conformationally restricted analogues of milnacipran, a weak NMDA receptor antagonist, were designed by a method based on allylic strain [34].
  • Effect of prolonged exposure to milnacipran on norepinephrine transporter in cultured bovine adrenal medullary cells [35].

Analytical, diagnostic and therapeutic context of F 2207

  • A multicenter study compared the antidepressant efficacy and the tolerance of two doses of milnacipran (50 mg and 100 mg/day) and amitriptyline (150 mg/day) in three parallel groups of 45 major depressive inpatients defined by Research Diagnostic Criteria [2].
  • The (Z)-enantiomer of midalcipran, at 0.1 microM, displaced to the right the concentration-effect curve of inhibition of release of [3H]5-HT elicited by electrical stimulation induced by LSD [36].
  • Milnacipran (30 and 60 mg/kg, PO) significantly reduced the duration of both the immobility time in the forced swimming test and the freezing time in the conditioned fear stress test in rats, which are animal behavioral models for depression and anxiety, respectively [25].
  • A subgroup analysis of hospitalized patients in the meta-analysis showed an advantage for milnacipran, suggesting that milnacipran is effective in more severe depression [37].
  • There are indications, both from the randomized clinical trials and from the phase IV programme, that milnacipran may have a comparatively rapid onset of action, showing clear signs of efficacy after one week of treatment [8].


  1. Peripheral nerve injury sensitizes the response to visceral distension but not its inhibition by the antidepressant milnacipran. Shin, S.W., Eisenach, J.C. Anesthesiology (2004) [Pubmed]
  2. Controlled comparison of two doses of milnacipran (F 2207) and amitriptyline in major depressive inpatients. Ansseau, M., von Frenckell, R., Mertens, C., de Wilde, J., Botte, L., Devoitille, J.M., Evrard, J.L., De Nayer, A., Darimont, P., Dejaiffe, G. Psychopharmacology (Berl.) (1989) [Pubmed]
  3. Efficacy of milnacipran in patients with fibromyalgia. Gendreau, R.M., Thorn, M.D., Gendreau, J.F., Kranzler, J.D., Ribeiro, S., Gracely, R.H., Williams, D.A., Mease, P.J., McLean, S.A., Clauw, D.J. J. Rheumatol. (2005) [Pubmed]
  4. Milnacipran in the treatment of bulimia nervosa: a report of 16 cases. El-Giamal, N., de Zwaan, M., Bailer, U., Strnad, A., Schüssler, P., Kasper, S. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (2003) [Pubmed]
  5. Pharmacokinetics of milnacipran in comparison with other antidepressants. Puozzo, C., Leonard, B.E. International clinical psychopharmacology. (1996) [Pubmed]
  6. Pharmacodynamics of milnacipran in young and elderly volunteers. Hindmarch, I., Rigney, U., Stanley, N., Briley, M. British journal of clinical pharmacology. (2000) [Pubmed]
  7. Preclinical pharmacology of milnacipran. Briley, M., Prost, J.F., Moret, C. International clinical psychopharmacology. (1996) [Pubmed]
  8. Japanese experience with dual-action antidepressants. Tajima, O. International clinical psychopharmacology. (2002) [Pubmed]
  9. Effect of chronic treatment with milnacipran on sleep architecture in rats compared with paroxetine and imipramine. Gervasoni, D., Panconi, E., Henninot, V., Boissard, R., Barbagli, B., Fort, P., Luppi, P.H. Pharmacol. Biochem. Behav. (2002) [Pubmed]
  10. Milnacipran for the drastic improvement of refractory pain in a patient without depressive symptoms: a case report. Kito, S., Nakajima, T., Koga, Y. Eur. Psychiatry (2005) [Pubmed]
  11. Prediction of antidepressant response to milnacipran by norepinephrine transporter gene polymorphisms. Yoshida, K., Takahashi, H., Higuchi, H., Kamata, M., Ito, K., Sato, K., Naito, S., Shimizu, T., Itoh, K., Inoue, K., Suzuki, T., Nemeroff, C.B. The American journal of psychiatry. (2004) [Pubmed]
  12. Lack of interaction of milnacipran with the cytochrome p450 isoenzymes frequently involved in the metabolism of antidepressants. Puozzo, C., Lens, S., Reh, C., Michaelis, K., Rosillon, D., Deroubaix, X., Deprez, D. Clinical pharmacokinetics. (2005) [Pubmed]
  13. The effect of milnacipran (serotonin noradrenaline reuptake inhibitor) on memory in Korsakoff's syndrome after encephalitis. Numata, S., Hongwei, S., Ueno, S., Ohmori, T. General hospital psychiatry. (2005) [Pubmed]
  14. The four-plates test: anxiolytic or analgesic paradigm? Ripoll, N., Hascoët, M., Bourin, M. Prog. Neuropsychopharmacol. Biol. Psychiatry (2006) [Pubmed]
  15. Acidic sphingomyelinase: relationship with antidepressant-induced desensitization of beta-adrenoceptors. Carre, J.B., Boutry, J.M., Baumann, N., Maurin, Y. Life Sci. (1988) [Pubmed]
  16. Double-blind comparative study of the action of repeated administration of milnacipran versus placebo on cognitive functions in healthy volunteers. Poirier, M.F., Galinowski, A., Amado, I., Longevialle, R., Bourdel, M.C., Tournoux, A., Serre, C., Loo, H. Human psychopharmacology. (2004) [Pubmed]
  17. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. Stahl, S.M., Grady, M.M., Moret, C., Briley, M. CNS spectrums. (2005) [Pubmed]
  18. Milnacipran. A review of its use in depression. Spencer, C.M., Wilde, M.I. Drugs (1998) [Pubmed]
  19. (+/-)-(Z)-2-(aminomethyl)-1-phenylcyclopropanecarboxamide derivatives as a new prototype of NMDA receptor antagonists. Shuto, S., Takada, H., Mochizuki, D., Tsujita, R., Hase, Y., Ono, S., Shibuya, N., Matsuda, A. J. Med. Chem. (1995) [Pubmed]
  20. Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications. Caccia, S. Clinical pharmacokinetics. (1998) [Pubmed]
  21. Chronic treatment with milnacipran reverses the impairment of synaptic plasticity induced by conditioned fear stress. Matsumoto, M., Tachibana, K., Togashi, H., Tahara, K., Kojima, T., Yamaguchi, T., Yoshioka, M. Psychopharmacology (Berl.) (2005) [Pubmed]
  22. Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Moret, C., Charveron, M., Finberg, J.P., Couzinier, J.P., Briley, M. Neuropharmacology (1985) [Pubmed]
  23. Effect of acute, short- and long-term milnacipran administration on rat locus coeruleus noradrenergic and dorsal raphe serotonergic neurons. Mongeau, R., Weiss, M., de Montigny, C., Blier, P. Neuropharmacology (1998) [Pubmed]
  24. Lack of effect of repeated administration of milnacipran, a double noradrenaline and serotonin reuptake inhibitor, on the beta-adrenoceptor-linked adenylate cyclase system in the rat cerebral cortex. Neliat, G., Bodinier, M.C., Panconi, E., Briley, M. Neuropharmacology (1996) [Pubmed]
  25. Neurochemical and behavioural characterization of milnacipran, a serotonin and noradrenaline reuptake inhibitor in rats. Mochizuki, D., Tsujita, R., Yamada, S., Kawasaki, K., Otsuka, Y., Hashimoto, S., Hattori, T., Kitamura, Y., Miki, N. Psychopharmacology (Berl.) (2002) [Pubmed]
  26. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. Iyengar, S., Webster, A.A., Hemrick-Luecke, S.K., Xu, J.Y., Simmons, R.M. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  27. Modulation of the extracellular 5-hydroxytryptamine brain concentrations by the serotonin and noradrenaline reuptake inhibitor, milnacipran. Microdialysis studies in rats. Bel, N., Artigas, F. Neuropsychopharmacology (1999) [Pubmed]
  28. Synthesis and biological activity of conformationally restricted analogues of milnacipran: (1S, 2R)-1-phenyl-2-[(R)-1-amino-2-propynyl]-N,N- diethylcyclopropanecarboxamide is a novel class of NMDA receptor channel blocker. Shuto, S., Ono, S., Imoto, H., Yoshii, K., Matsuda, A. J. Med. Chem. (1998) [Pubmed]
  29. Controlled comparison of milnacipran and fluoxetine in major depression. Ansseau, M., Papart, P., Troisfontaines, B., Bartholomé, F., Bataille, M., Charles, G., Schittecatte, M., Darimont, P., Devoitille, J.M., De Wilde, J. Psychopharmacology (Berl.) (1994) [Pubmed]
  30. Interest of a loading dose of milnacipran in endogenous depressive inpatients. Comparison with the standard regimen and with fluvoxamine. Ansseau, M., von Frenckell, R., Gérard, M.A., Mertens, C., De Wilde, J., Botte, L., Devoitille, J.M., Evrard, J.L., De Nayer, A., Darimont, P. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (1991) [Pubmed]
  31. Acute effect of milnacipran on the relationship between the locus coeruleus noradrenergic and dorsal raphe serotonergic neuronal transmitters. Bandoh, T., Hayashi, M., Ino, K., Takada, S., Ushizawa, D., Hoshi, K. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (2004) [Pubmed]
  32. (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC), a new class of NMDA-receptor antagonist: molecular design by a novel conformational restriction strategy. Shuto, S., Yoshii, K., Matsuda, A. Jpn. J. Pharmacol. (2001) [Pubmed]
  33. Effect of pindolol and milnacipran versus milnacipran and placebo on plasma prolactin and adrenocorticotrophic hormone in depressed subjects. Isaac, M.B., Isaac, M.T. Human psychopharmacology. (2003) [Pubmed]
  34. A method for designing conformationally restricted analogues based on allylic strain: synthesis of a novel class of noncompetitive NMDA receptor antagonists having the acrylamide structure. Ohmori, Y., Yamashita, A., Tsujita, R., Yamamoto, T., Taniuchi, K., Matsuda, A., Shuto, S. J. Med. Chem. (2003) [Pubmed]
  35. Effect of prolonged exposure to milnacipran on norepinephrine transporter in cultured bovine adrenal medullary cells. Shinkai, K., Yoshimura, R., Toyohira, Y., Ueno, S., Tsutsui, M., Nakamura, J., Yanagihara, N. Biochem. Pharmacol. (2005) [Pubmed]
  36. Sensitivity of the response of 5-HT autoreceptors to drugs modifying synaptic availability of 5-HT. Moret, C., Briley, M. Neuropharmacology (1988) [Pubmed]
  37. Clinical efficacy of milnacipran: placebo-controlled trials. Lecrubier, Y., Pletan, Y., Solles, A., Tournoux, A., Magne, V. International clinical psychopharmacology. (1996) [Pubmed]
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