The Discovery of Citalopram and Its Refinement to Escitalopram

Analogue-Based Drug Discovery III

Volumn , Issue , 2012, Pages 269-294

  Bøgesø, Klaus P ^a   Sánchez, Connie ^b  

^a H LUNDBECK A S   (Denmark)

^b LUNDBECK RESEARCH USA   (United States)

Author keywords

Allosteric; Binding site; Citalopram; Escitalopram; Norepinephrine; Orthosteric; Serotonin; Transporter

Indexed keywords

EID: 84885533214     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527651085.ch11     Document Type: Chapter

References (91)

1. Childers, W.E., Jr., and Rotella, D.P. (2011) Selective serotonin uptake inhibitors for the treatment of depression, in Analogue- Based Drug Discovery II (eds J. Fischer, and C.R. Ganellin), Wiley-VCH Verlag GmbH, Weinheim, pp. 269-295.
2. Bang-Andersen, B. and Bøgesø, K.P. (2010) Dopamine and serotonin, in Textbook of Drug Design and Discovery, 4th edn (eds P. Krogsgaard-Larsen, K. Strømgaard, and U. Madsen), CRC Press, Boca Raton, FL,, pp. 299-312.
3. H. Lundbeck A/S (2010) Cipralex1: Building a Success. H. Lundbeck A/S, Valby, Denmark.
4. Pedersen, V. and Bøgesø, K.P. (1998) Drug hunting, in The Psychopharmacologists II (ed. D. Healy), Chapman and Hall, London, UK, pp. 561-579.
5. Carlsson, A., Corrodi, H., Fuxe, K., and Hokfelt, T. (1969) Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-a-ethyl-meta-tyramine. Eur. J. Pharmacol., 5, 357-366.
6. Chen, F., Larsen, M.B., Neubauer, H.A., Sanchez, C., Plenge, P., and Wiborg, O. (2005) Characterization of an allosteric citalopram-binding site at the serotonin transporter. J. Neurochem., 92, 21-28.
7. Bigler, A.J., Bøgesø, K.P., Toft, A., and Hansen, V. (1977) Quantitative structure- activity relationships in a series of selective 5-HTuptake inhibitors. Eur. J. Med. Chem., 12, 289-295.
8. Bøgesø, K.P., Christensen, A.V., Hyttel, J., and Liljefors, T. (1985) 3-Phenyl-1- indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake. J. Med. Chem., 28, 1817-1828.
9. Hyttel, J. (1977) Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu 10-171. Psychopharmacology, 51, 225-233.
10. 3H]-5-HT uptake in rat brain synaptosomes in vitro. Psychopharmacology, 60, 13-18.
11. Hyttel, J., Arnt, J., and Sanchez, C. (1995) The pharmacology of citalopram. Rev. Contemp. Pharmacother., 6, 271-285.
12. 3H]citalopram binding to the 5-HT transporter from brain and platelets. Eur. J. Pharmacol., 206, 243-250.
13. Hyttel, J. (1977) Effect of a selective 5-HT uptake inhibitor-Lu 10-171-on rat brain 5-HT turnover. Acta Pharmacol. Toxicol., 40, 439-446.
14. Carlsson, A. and Lindqvist, M. (1978) Effects of antidepressant agents on the synthesis of brain monoamines. J. Neural Transm., 43, 73-91.
15. Christensen, A.V., Fjalland, B., Pedersen, V., Danneskiold-Samsøe, P., and Svendsen, O. (1977) Pharmacology of a new phthalane (Lu 10-171), with specific 5-HT uptake inhibiting properties. Eur. J. Pharmacol., 41, 153-162.
16. Porsolt, R.D., Bertin, A., Blavet, N., Deniel, M., and Jalfre, M. (1979) Immobility induced by forced swimming in rats: effects of agents which modify central catecholamine and serotonin activity. Eur. J. Pharmacol., 57, 201-210.
17. Joubert, A.F., Sanchez, C., and Larsen, F. (2000) Citalopram. Hum. Psychopharmacol., 15, 439-451.
18. Bezchlibnyk-Butler, K., Aleksic, I., and Kennedy, S.H. (2000) Citalopram-a review of pharmacological and clinical effects. J. Psychiatry Neurosci., 25, 241-254.
19. Baldwin, D., and Johnson, F.N. (1995) Tolerability and safety of citalopram. Rev. Contemp. Pharmacother., 6, 315.
20. Muldoon, C. (1996) The safety and tolerability of citalopram. Int. Clin. Psychopharmacol., 11 (Suppl. 1), 35-40.
21. Harrington, P.J. (2011) Lexapro1 (escitalopram oxalate), in Pharmaceutical Process Chemistry for Synthesis, Rethinking the Routes to Scale-Up, John Wiley and Sons, Inc., Hoboken, NJ, pp. 30-91.
22. Elati, C.R., Kolla, N., Vankawala, P.J., Gangula, S., Chalamala, S., Sundaram, V., Bhattacharya, A., Vurimidi, H., and Mathad, V.T. (2007) Substrate modification approach to achieve efficient resolution: didesmethylcitalopram: a key intermediate for escitalopram. Org. Process Res. Dev., 11, 289-292.
23. Dancer, R.J., and de Diego, H.L. (2009) Attempted resolution of citalopram using (-)-O, O0-di-p-toluoyl-(R, R)-tartaric acid, and reflections on an alkylation reaction; comment on an article by Elati et al. Org. Process Res. Dev., 13, 23-33.
24. Dancer, R.J., and de Diego, H.L. (2009) Response to the comments by Elati et al. in response to our article examining one of their previous papers. Org. Process Res. Dev., 13, 38-43.
25. Elati, C.R., Kolla, N., and Mathad, V.T. (2009) Response to Dancer's comments on our article "Substrate modification approach to achieve efficient resolution: didesmethylcitalopram: a key intermediate for escitalopram." Org. Process Res. Dev., 13, 34-37.
26. Hyttel, J., Bogeso, K.P., Perregaard, J., and Sanchez, C. (1992) The pharmacological effect of citalopram residues in the (S)- (+)-enantiomer. J. Neural Transm., 88, 157-160.
27. Sanchez, C. (2003) R-Citalopram attenuates anxiolytic effects of escitalopram in a rat ultrasonic vocalisation model. Eur. J. Pharmacol., 464, 155-158.
28. Sidhu, J., Priskorn, M., Poulsen, M., Segonzac, A., Grollier, G., and Larsen, F. (1997) Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans. Chirality, 9, 686-692.
29. Mørk, A., Kreilgaard, M., and Sanchez, C. (2003) The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats. Neuropharmacology, 45, 167-173.
30. Sanchez, C., Bergqvist, P.B., Brennum, L.T., Gupta, S., Hogg, S., Larsen, A., and Wiborg, O. (2003) Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology, 167, 353-362.
31. El Mansari, M., Sanchez, C., Chouvet, G., Renaud, B., and Haddjeri, N. (2005) Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain. Neuropsychopharmacology, 30, 1269-1277.
32. El Mansari, M., Wiborg, O., Mnie-Filali, O., Benturquia, N., Sanchez, C., and Haddjeri, N. (2007) Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. Int. J. Neuropsychopharmacol., 10, 31-40.
33. Mnie-Filali, O., Faure, C., Mansari, M.E., Lambas-Senas, L., Berod, A., Zimmer, L., Sanchez, C., and Haddjeri, N. (2007) RCitalopram prevents the neuronal adaptive changes induced by escitalopram. Neuroreport, 18, 1553-1556.
34. Sanchez, C., Bogeso, K.P., Ebert, B., Reines, E.H., and Braestrup, C. (2004) Escitalopram versus citalopram: the surprising role of the R-enantiomer. Psychopharmacology, 174, 163-176.
35. Sanchez, C. (2006) The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of Scitalopram. Basic Clin. Pharmacol. Toxicol., 99, 91-95.
36. Zhong, H., Haddjeri, N., and Sanchez, C. (2012) Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter-a review of current understanding of its mechanism of action. Psychopharmacology, 219 (1), 1-13.
37. Cremers, T.I.F.H. and Westerink, B.H.C. (2003) Pharmacological difference between escitalopram and citalopram. Int. J. Psychiatry Clin. Pract., 7, 306..
38. Lucki, I. and Brown, K. (2003) Different roles of the enantiomers of citalopram on serotonin transmission. Biol. Psychiatry, 53, 45S.
39. Altamirano, A.V., and Frazer, A. (2005) Comparison of the effects of the enantiomers of citalopram on the clearance of exogenous serotonin. Poster presented at the SoPB 2005.
40. Schilstrom, B., Konradsson-Geuken, A., Ivanov, V., Gertow, J., Feltmann, K., Marcus, M.M., Jardemark, K., and Svensson, T.H. (2011) Effects of Scitalopram, citalopram, and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, Nmethyl- D-aspartate receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat. Synapse, 65, 357-367.
41. Mnie-Filali, O., El, M.M., Espana, A., Sanchez, C., and Haddjeri, N. (2006) Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity. Neurosci. Lett., 395, 23-27.
42. Sanchez, C., and Kreilgaard, M. (2004) RCitalopram inhibits functional and 5- HTP-evoked behavioural responses to the SSRI, escitalopram. Pharmacol. Biochem. Behav., 77, 391-398.
43. Storustovu, S., Sanchez, C., Porzgen, P., Brennum, L.T., Larsen, A.K., Pulis, M., and Ebert, B. (2004) R-Citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter. Br. J. Pharmacol., 142, 172-180.
44. Bien, E., Gruca, P., and Papp, M. (2003) RCitalopram attenuates the anxiolytic-like activity of escitalopram in two animal models. Behav. Pharmacol., 14 (Suppl. 1), S37.
45. Fish, E.W., Faccidomo, S., Gupta, S., and Miczek, K.A. (2004) Anxiolytic-like effects of escitalopram, citalopram, and Rcitalopram in maternally separated mouse pups. J. Pharmacol. Exp. Ther., 308, 474-480.
46. Sanchez, C., Gruca, P., Bien, E., and Papp, M. (2003) R-Citalopram counteracts the effect of escitalopram in a rat conditioned fear stress model of anxiety. Pharmacol. Biochem. Behav., 75, 903-907.
47. Mitchell, P.J., Hogg, S., and Sanchez, C. (2004) Agonistic behaviour of resident rats after acute and chronic treatment with S (+)- and R(-)-citalopram. Int. J. Neuropsychopharmacol., 7, S187. Poster presented at the 24th CINP, June 20-24, 2004, Paris, France, P01.206.
48. Sanchez, C., Gruca, P., and Papp, M. (2003) R-Citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model. Behav. Pharmacol., 14, 465-470.
49. Zhong, H., Hansen, K.B., Boyle, N.J., Han, K., Muske, G., Huang, X., Egebjerg, J., and Sanchez, C. (2009) An allosteric binding site at the human serotonin transporter mediates the inhibition of escitalopram by R-citalopram: kinetic binding studies with the ALI/VFL-SI/TT mutant. Neurosci. Lett., 462, 207-212.
50. Neubauer, H.A., Hansen, C.G., and Wiborg, O. (2006) Dissection of an allosteric mechanism on the serotonin transporter: a cross-species study. Mol. Pharmacol., 69, 1242-1250.
51. Klein, N., Sacher, J., Geiss-Granadia, T., Mossaheb, N., Attarbaschi, T., Lanzenberger, R., Spindelegger, C., Holik, A., Asenbaum, S., Dudczak, R., Tauscher, J., and Kasper, S. (2007) Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: an 123IADAM SPECTstudy. Psychopharmacology, 191, 333-339.
52. Kasper, S., Sacher, J., Klein, N., Mossaheb, N., Attarbaschi-Steiner, T., Lanzenberger, R., Spindelegger, C., Asenbaum, S., Holik, A., and Dudczak, R. (2009) Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram. Int. Clin. Psychopharmacol., 24, 119-125.
53. Bøgesø, K.P. (1983) Neuroleptic activity and dopamine-uptake inhibition in 1- piperazino-3-phenylindans. J. Med. Chem., 26, 935-947.
54. Bøgesø, K.P., Hyttel, J., Christensen, A.V., and Arnt, J. (1986) Chirality as determinant for neuroleptic or antidepressant action of drugs, in Innovative Approaches in Drug Research, vol. 9 (ed. A.F. Harms), Elsevier, Amsterdam, pp. 371-392.
55. Smith, D.F. (1986) The stereoselectivity of serotonin uptake in brain tissue and blood platelets: the topography of the serotonin uptake area. Neurosci. Biobehav. Rev., 10, 37-46.
56. Gundertofte, K., Liljefors, T., and Bøgesø, K.P. (1997) A stereoselective pharmacophoric model of the serotonin reuptake site, in Computer-Assisted Lead Finding and Optimization (eds H. van de Waterbeemd, B. Testa, and G. Folkers), VHCA, Basel, pp. 443-459.
57. Koldso, H., Severinsen, K., Tran, T.T., Celik, L., Jensen, H.H., Wiborg, O., Schiott, B., and Sinning, S. (2010) The two enantiomers of citalopram bind to the human serotonin transporter in reversed orientations. J. Am. Chem. Soc., 132, 1311-1322.
58. Eildal, J.N., Andersen, J., Kristensen, A.S., Jorgensen, A.M., Bang-Andersen, B., Jorgensen, M., and Stromgaard, K. (2008) From the selective serotonin transporter inhibitor citalopram to the selective norepinephrine transporter inhibitor talopram: synthesis and structure-activity relationship studies. J. Med. Chem., 51, 3045-3048.
59. Andersen, J., Stuhr-Hansen, N., Zachariassen, L., Toubro, S., Hansen, S. M., Eildal, J.N., Bond, A.D., Bogeso, K.P., Bang-Andersen, B., Kristensen, A.S., and Stromgaard, K. (2011) Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. Proc. Natl. Acad. Sci. USA, 108, 12137-12142.
60. -- dependent neurotransmitter transporters. Nature, 437, 215-223.
61. Jorgensen, A.M., Tagmose, L., Jorgensen, A.M., Topiol, S., Sabio, M., Gundertofte, K., Bogeso, K.P., and Peters, G.H. (2007) Homology modeling of the serotonin transporter: insights into the primary escitalopram-binding site. ChemMedChem, 2, 815-826.
62. --dependent neurotransmitter transporters in a membrane-aqueous system. ChemMedChem, 2, 827-840.
63. Andersen, J., Olsen, L., Hansen, K.B., Taboureau, O., Jorgensen, F.S., Jorgensen, A.M., Bang-Andersen, B., Egebjerg, J., Stromgaard, K., and Kristensen, A.S. (2010) Mutational mapping and modeling of the binding site for (S)-citalopram in the human serotonin transporter. J. Biol. Chem., 285, 2051-2063.
64. Andersen, J., Taboureau, O., Hansen, K. B., Olsen, L., Egebjerg, J., Stromgaard, K., and Kristensen, A.S. (2009) Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438 in recognition of citalopram and tricyclic antidepressants. J. Biol. Chem., 284 10276-10284.
65. Singh, S.K., Yamashita, A., and Gouaux, E. (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature, 448, 952-956.
66. Zhou, Z., Zhen, J., Karpowich, N.K., Goetz, R.M., Law, C.J., Reith, M.E., and Wang, D.N. (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science, 317, 1390-1393.
67. Jorgensen, A.M., and Topiol, S. (2008) Driving forces for ligand migration in the leucine transporter. Chem. Biol. Drug Des., 72, 265-272.
68. Zhou, Z., Zhen, J., Karpowich, N.K., Law, C.J., Reith, M.E., and Wang, D.N. (2009) Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures. Nat. Struct. Mol. Biol., 16, 652-657.
69. Bøgesø, K.P., Bregnedal, P., Juhl, K., Zhong, H., and Wiborg, O. (2010) New naphthalene derivatives of citalopram discriminate between the primary and the allosteric binding sites at the human serotonin transporter. Basic Clin. Pharmacol. Toxicol., 107 (Suppl. 1), 210.
70. Lau, T., Horschitz, S., Berger, S., Bartsch, D., and Schloss, P. (2008) Antidepressantinduced internalization of the serotonin transporter in serotonergic neurons. FASEB J., 22, 1702-1714.
71. Kittler, K., Lau, T., and Schloss, P. (2010) Antagonists and substrates differentially regulate serotonin transporter cell surface expression in serotonergic neurons. Eur. J. Pharmacol., 629, 63-67.
72. Mnie-Filali, O., Mansari, M.E., Sanchez, C., and Haddjeri, N. (2009) Therapeutic relevance of the allosteric modulation of the 5-HT transporter. Curr. Signal Transduct. Ther., 4, 82-87.
73. Zhong, H., Sanchez, C., and Caron, M.G. (2011) Consideration of allosterism and interacting proteins in the physiological functions of the serotonin transporter. Biochem. Pharmacol., 83 (4), 435-442.
74. Burke, W.J., Gergel, I., and Bose, A. (2002) Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients J. Clin. Psychiatry, 63, 331-336.
75. Lepola, U.M., Loft, H., and Reines, E.H. (2003) Escitalopram (10-20mg/day) is effective and well tolerated in a placebocontrolled study in depression in primary care. Int. Clin. Psychopharmacol., 18, 211-217.
76. Moore, N., Verdoux, H., and Fantino, B. (2005) Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int. Clin. Psychopharmacol., 20, 131-137.
77. Yevtushenko, V.Y., Belous, A.I., Yevtushenko, Y.G., Gusinin, S.E., Buzik, O.J., and Agibalova, T.V. (2007) Efficacy and tolerability of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, prospective, randomized, double-blind, activecontrolled study in adult outpatients. Clin. Ther., 29, 2319-2332.
78. Kennedy, S.H., Andersen, H.F., and Thase, M.E. (2009) Escitalopram in the treatment of major depressive disorder: a meta-analysis. Curr. Med. Res. Opin., 25, 161-175.
79. Montgomery, S., Hansen, T., and Kasper, S. (2011) Efficacy of escitalopram compared to citalopram: a meta-analysis. Int. J. Neuropsychopharmacol., 14, 261-268.
80. Boulenger, J.P., Huusom, A.K., Florea, I., Baekdal, T., and Sarchiapone, M. (2006) A comparative study of the efficacy of longterm treatment with escitalopram and paroxetine in severely depressed patients. Curr. Med. Res. Opin., 22, 1331-1341.
81. Boulenger, J.P., Hermes, A., Huusom, A.K., and Weiller, E. (2010) Baseline anxiety effect on outcome of SSRI treatment in patients with severe depression: escitalopram vs paroxetine. Curr. Med. Res. Opin., 26, 605-614.
82. Kasper, S., Baldwin, D.S., Larsson, L.S., and Boulenger, J.P. (2009) Superiority of escitalopram to paroxetine in the treatment of depression. Eur. Neuropsychopharmacol., 19, 229-237.
83. Khan, A., Bose, A., Alexopoulos, G.S., Gommoll, C., Li, D., and Gandhi, C. (2007) Double-blind comparison of escitalopram and duloxetine in the acute treatment of major depressive disorder. Clin. Drug Invest., 27, 481-492.
84. Montgomery, S.A., and Andersen, H.F. (2006) Escitalopram versus venlafaxine XR in the treatment of depression. Int. Clin. Psychopharmacol., 21, 297-309.
85. Kennedy, S.H., Andersen, H.F., and Lam, R.W. (2006) Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis. J. Psychiatry Neurosci., 31, 122-131.
86. Wade, A., Gembert, K., and Florea, I. (2007) A comparative study of the efficacy of acute and continuation treatment with escitalopram versus duloxetine in patients with major depressive disorder. Curr. Med. Res. Opin., 23, 1605-1614.
87. Cipriani, A., Furukawa, T.A., Salanti, G., Geddes, J.R., Higgins, J.P., Churchill, R., Watanabe, N., Nakagawa, A., Omori, I.M., McGuire, H., Tansella, M., and Barbui, C. (2009) Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet, 373, 746-758.
88. Baldwin, D.S., Huusom, A.K., and Maehlum, E. (2006) Escitalopram and paroxetine in the treatment of generalised anxiety disorder: randomised, placebocontrolled, double-blind study. Br. J. Psychiatry, 189, 264-272.
89. Lader, M., Stender, K., Burger, V., and Nil, R. (2004) Efficacy and tolerability of escitalopram in 12- and 24-week treatment of social anxiety disorder: randomised, double-blind, placebo-controlled, fixeddose study. Depress. Anxiety, 19, 241-248.
90. Hayes, B.D., Klein-Schwartz, W., Clark, R.F., Muller, A.A., and Miloradovich, J.E. (2010) Comparison of toxicity of acute overdoses with citalopram and escitalopram. J. Emerg. Med., 39, 44-48.
91. Yilmaz, Z., Ceschi, A., Rauber-Luthy, C., Sauer, O., Stedtler, U., Prasa, D., Seidel, C., Hackl, E., Hoffmann-Walbeck, P., Gerber-Zupan, G., Bauer, K., Kupferschmidt, H., Kullak-Ublick, G.A., and Wilks, M. (2010) Escitalopram causes fewer seizures in human overdose than citalopram. Clin. Toxicol., 48, 207-212.