Diclofensine Explained

Diclofensine (Ro 8-4650) was developed by Hoffmann-La Roche in the 1970s[1] in the search for a new antidepressant. It was found that the (S)-isomer was responsible for activity.[2] Diclofensine is a stimulant drug which acts as a triple monoamine reuptake inhibitor,[3] [4] primarily inhibiting the reuptake of dopamine[5] and norepinephrine,[6] with affinities (Ki) of 16.8 nM, 15.7 nM, and 51 nM for DAT, NET, and SERT (dopamine, norepinephrine and serotonin transporters), respectively.[7] It was found to be an effective antidepressant in human trials,[8] [9] [10] with relatively few side effects,[11] but was ultimately dropped from clinical development, possibly due to concerns about its abuse potential.[12] [13]

Diclofensine is chemically a tetrahydroisoquinoline (THIQ) derivative, as is nomifensine.

Synthesis

The condensation of m-anisaldehyde [591-31-1] (1) with methylamine gives N-methyl-3-methoxybenzenemethanimine [16928-30-6]. Reduction of this Schiff-base intermediate with sodium borohydride gives (3-methoxybenzyl)methylamine [41789-95-1] (2). Alkylation of this with 3,4-dichlorophenacylbromide [2632-10-2] (3) would give CID:59580342 (4). Reduction of the benzoyl ketone with sodium borohydride gives the alcohol [802051-24-7] (5). Acid catalyzed intramolecular cyclization then completes the synthesis of the 4-aryl-THIQ derivative, diclofensine (6).

See also

Notes and References

  1. US . 3947456 A . Patent . Substituted 4-Phenyl Isoquinolines . 1976-03-30 . 1970-12-29 . 1970-01-06 . Alfred Rheiner . Hoffman-La Roche Inc. .
  2. Book: Crossley . Roger . Chirality and the Biological Activity of Drugs . 1995 . CRC Press, Inc. . 2000 Corporate Blvd., N.W., Boca Raton, Florida 33431 . 978-0-8493-9140-8 . 138 .
  3. Keller HH, Schaffner R, Carruba MO, Burkard WP, Pieri M, Bonetti EP, Scherschlicht R, Da Prada M, Haefely WE . 6 . Diclofensine (Ro 8-4650)--a potent inhibitor of monoamine uptake: biochemical and behavioural effects in comparison with nomifensine . Advances in Biochemical Psychopharmacology . 31 . 249–63 . 1982 . 6979165 .
  4. Omer LM . Pilot trials with diclofensine, a new psychoactive drug in depressed patients . International Journal of Clinical Pharmacology, Therapy, and Toxicology . 20 . 7 . 320–6 . July 1982 . 7107085 .
  5. Di Renzo G, Amoroso S, Taglialatela M, Canzoniero LM, Maida P, Lombardi G, Annunziato L . Pure uptake blockers of dopamine can reduce prolactin secretion: studies with diclofensine . Life Sciences . 42 . 21 . 2161–9 . 1988 . 2968488 . 10.1016/0024-3205(88)90131-2 .
  6. Gasić S, Korn A, Eichler HG . Effect of diclofensine, a novel antidepressant, on peripheral adrenergic function . Clinical Pharmacology and Therapeutics . 39 . 5 . 582–5 . May 1986 . 3698467 . 10.1038/clpt.1986.100 . 34977195 .
  7. Andersen PH . The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action . European Journal of Pharmacology . 166 . 3 . 493–504 . August 1989 . 2530094 . 10.1016/0014-2999(89)90363-4 .
  8. Cherpillod C, Omer LM . A controlled trial with diclofensine, a new psychoactive drug, in the treatment of depression . The Journal of International Medical Research . 9 . 5 . 324–9 . 1981 . 7028532 . 10.1177/030006058100900505 . 41618656 .
  9. Omer OL, Díaz-Olivera M, Ismail S . Therapeutic efficacy and tolerance of diclofensine in psychoreactive depression--a double-blind comparison with placebo . Methods and Findings in Experimental and Clinical Pharmacology . 6 . 3 . 147–51 . March 1984 . 6379345 .
  10. Funke HJ, Holtmann W, Ismail S, Jansen W, Leonhardt KF, Muth H, Omer LM, O'Connolly M, Ramm H . 6 . Double-blind comparison of diclofensine with nomifensine in outpatients with dysphoric mood . Pharmacopsychiatry . 19 . 3 . 120–3 . May 1986 . 3725890 . 10.1055/s-2007-1017168 . 36360683 .
  11. Culig J, Ehsanullah RS, Hallett C, Iliopoulou A, Matheson I, Turner P . A clinical pharmacological comparison of diclofensine (Ro 8-4650) with nomifensine and amitriptyline in normal human volunteers . British Journal of Clinical Pharmacology . 15 . 5 . 537–43 . May 1983 . 6860528 . 1427714 . 10.1111/j.1365-2125.1983.tb02087.x .
  12. Lamb RJ, Griffiths RR . Self-administration in baboons and the discriminative stimulus effects in rats of bupropion, nomifensine, diclofensine and imipramine . Psychopharmacology . 102 . 2 . 183–90 . 1990 . 2125734 . 10.1007/bf02245920 . 25043692 .
  13. Nakachi N, Kiuchi Y, Inagaki M, Inazu M, Yamazaki Y, Oguchi K . Effects of various dopamine uptake inhibitors on striatal extracellular dopamine levels and behaviours in rats . European Journal of Pharmacology . 281 . 2 . 195–203 . August 1995 . 7589207 . 10.1016/0014-2999(95)00246-h .

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