Niaprazine Explained

Niaprazine (INN) (brand name Nopron) is a sedative-hypnotic drug of the phenylpiperazine group.[1] [2] It has been used in the treatment of sleep disturbances since the early 1970s in several European countries including France, Italy, and Luxembourg.[3] [4] It is commonly used with children and adolescents on account of its favorable safety and tolerability profile and lack of abuse potential.[5] [6] [7] [8] [9] [10]

Originally believed to act as an antihistamine and anticholinergic,[11] niaprazine was later discovered to have low or no binding affinity for the H1 and mACh receptors (Ki = > 1 μM), and was instead found to act as a potent and selective 5-HT2A and α1-adrenergic receptor antagonist (Ki = 75 nM and 86 nM, respectively).[12] It possesses low or no affinity for the 5-HT1A, 5-HT2B, D2, and β-adrenergic, as well as at SERT and VMAT (Ki = all > 1 μM), but it does have some affinity for the α2-adrenergic receptor (Ki = 730 nM).

Niaprazine has been shown to metabolize to the compound para-fluorophenylpiperazine (pFPP) in a similar manner to how trazodone and nefazodone metabolize to meta-chlorophenylpiperazine (mCPP).[13] [14] It is unclear what role, if any, pFPP plays in the clinical effects of niaprazine. However, from animal studies it is known that pFPP, unlike niaprazine, does not produce sedative effects, and instead exerts a behavioral profile indicative of serotonergic activation.

Synthesis

A Mannich reaction using 4-fluorophenylpiperazine (1), 1,3,5-trioxane (2) and acetone gives the ketone (4). Reaction with hydroxylamine produces the oxime, (5), which is reduced with lithium aluminium hydride to give the amine (6). Amide formation with nicotinic acid (7), activated as its acid chloride, yields nilaprazine.[15] [16]

Notes and References

  1. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014. Springer. 978-1-4757-2085-3. 862–.
  2. Book: Kent A, Billiard M. Sleep: physiology, investigations, and medicine . Kluwer Academic/Plenum . New York . 2003 . 978-0-306-47406-4 .
  3. Book: Swiss Pharmaceutical Society . Index Nominum 2000: International Drug Directory (Book with CD-ROM) . Medpharm Scientific Publishers . Boca Raton . 2000 . 978-3-88763-075-1 .
  4. Book: Triggle DJ . Dictionary of Pharmacological Agents . Chapman & Hall/CRC . Boca Raton . 1996 . 978-0-412-46630-4 .
  5. Franzoni E, Masoni P, Mambelli M, Marzano P, Donati C . [Niaprazine in behavior disorders in children. Double-blind comparison with placebo] . it . La Pediatria Medica e Chirurgica: Medical and Surgical Pediatrics . 9 . 2 . 185–7 . 1987 . 2958783 .
  6. Bodiou C, Bavoux F . [Niaprazine and side effects in pediatrics. Cooperative evaluation of French centers of pharmacovigilance] . fr . Thérapie . 43 . 4 . 307–11 . 1988 . 2903572 .
  7. Ottaviano S, Giannotti F, Cortesi F . The effect of niaprazine on some common sleep disorders in children. A double-blind clinical trial by means of continuous home-videorecorded sleep . Child's Nervous System . 7 . 6 . 332–5 . October 1991 . 1837245 . 10.1007/bf00304832. 35908448 .
  8. Montanari G, Schiaulini P, Covre A, Steffan A, Furlanut M . Niaprazine vs chlordesmethyldiazepam in sleep disturbances in pediatric outpatients . Pharmacological Research . 25 . 83–4 . 1992 . Suppl 1 . 1354861 . 10.1016/1043-6618(92)90551-l.
  9. Younus M, Labellarte MJ . Insomnia in children: when are hypnotics indicated? . Paediatric Drugs . 4 . 6 . 391–403 . 2002 . 12038875 . 10.2165/00128072-200204060-00006. 33340367 .
  10. Mancini J, Thirion X, Masut A, etal . Anxiolytics, hypnotics, and antidepressants dispensed to adolescents in a French region in 2002 . Pharmacoepidemiology and Drug Safety . 15 . 7 . 494–503 . July 2006 . 16700077 . 10.1002/pds.1258. 24273650 .
  11. Duchene-Marullaz P, Rispat G, Perriere JP, Hache J, Labrid C . [Some pharmacodynamical properties of niaprazine, a new antihistaminic agent] . fr . Thérapie . 26 . 6 . 1203–9 . 1971 . 4401719 .
  12. Scherman D, Hamon M, Gozlan H, etal . Molecular pharmacology of niaprazine . Progress in Neuro-psychopharmacology & Biological Psychiatry . 12 . 6 . 989–1001 . 1988 . 2853885 . 10.1016/0278-5846(88)90093-0. 40566589 .
  13. Keane PE, Strolin Benedetti M, Dow J . The effect of niaprazine on the turnover of 5-hydroxytryptamine in the rat brain . Neuropharmacology . 21 . 2 . 163–9 . February 1982 . 6460945 . 10.1016/0028-3908(82)90157-5. 22310059 .
  14. Garattini S, Mennini T . Critical notes on the specificity of drugs in the study of metabolism and functions of brain monoamines . International Review of Neurobiology . 29 . 259–80 . 1988 . 3042665 . 10.1016/s0074-7742(08)60089-6 . 9780123668295 .
  15. US . 3712893 . J Simond, J Moleyre, R Mauvernay, N Busch . Butyl-piperazine derivatives . patent . 1973-01-23 . 1969-11-10 . Centre Europeen de Recherches Mauvernay.
  16. Web site: Niaprazine . Pharmaceutical Substances . Thieme . 2024-07-17.

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