Luzindole Explained

Luzindole (N-0774; N-acetyl-2-benzyltryptamine), is a drug used in scientific research to study the role of melatonin in the body. Luzindole acts as a selective melatonin receptor antagonist,^[1] with approximately 11- to 25-fold greater affinity for the MT₂ over the MT₁ receptor.^{[2] [3]} In animal studies, it has been observed to disrupt the circadian rhythm as well as produce antidepressant effects.^{[2] [4]}

Synthesis

Although the "hydrogen bomb" method was reported as 54% yield by Dubococvich, Boehringer Sohn achieved 96% for this step. The difference is that B.I. conducted their hydrogenation under normal pressure at 50°C for 5 hours, whereas Dubocovich conducted theirs at 100 lbs/in2 hydrogen heated to 35°C. This proves that the hydrogenation step proceeds favorably under milder conditions. The Pictet–Spengler reaction between tryptamine [61-54-1] (1) and benzaldehyde gives 1-Phenyl-tetrahydrocarboline [3790-45-2] (2). Catalytic hydrogenation leads to 2-Benzyltryptamine [22294-23-1] (3). Acylation with acetic anhydride only gave 21% yield of Luzindole (4).2-iodoaniline [615-43-0] (1)Propargylbenzene [10147-11-2] (2)2-(3-phenylprop-1-ynyl)aniline, PC85868179 (3)2-benzylindole [3377-72-8] (4)1-Dimethylamino-2-nitroethylene [1190-92-7] (5)(6)

One pot Luzindole synthesis:^[5]

Notes and References

1. Dubocovich ML . Luzindole (N-0774): a novel melatonin receptor antagonist . The Journal of Pharmacology and Experimental Therapeutics . 246 . 3 . 902–10 . September 1988 . 2843633 .
2. Dubocovich ML, Yun K, Al-Ghoul WM, Benloucif S, Masana MI . Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms . The FASEB Journal . 12 . 12 . 1211–20 . September 1998 . 9737724 . 10.1096/fasebj.12.12.1211 . free . 566199 .
3. Browning C, Beresford I, Fraser N, Giles H . Pharmacological characterization of human recombinant melatonin mt(1) and MT(2) receptors . . 129 . 5 . 877–86 . March 2000 . 10696085 . 1571913 . 10.1038/sj.bjp.0703130 .
4. Dubocovich ML, Mogilnicka E, Areso PM . Antidepressant-like activity of the melatonin receptor antagonist, luzindole (N-0774), in the mouse behavioral despair test . European Journal of Pharmacology . 182 . 2 . 313–25 . July 1990 . 2168835 . 10.1016/0014-2999(90)90290-M.
5. Righi, Marika; Topi, Francesca; Bartolucci, Silvia; Bedini, Annalida; Piersanti, Giovanni; Spadoni, Gilberto (2012). "Synthesis of Tryptamine Derivatives via a Direct, One-Pot Reductive Alkylation of Indoles". The Journal of Organic Chemistry. 77 (14): 6351–6357. doi:10.1021/jo3010028.