Niaprazine

Niaprazine

Clinical data
Trade names	Nopron
Other names	CERM-1709
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	N05CM16 ( WHO )
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life	~4.5 hours
Identifiers
IUPAC name N-{4-[4-(4-fluorophenyl)piperazin- 1-yl]butan- 2-yl}pyridine- 3-carboxamide
CAS Number	27367-90-4
PubChem CID	71919
ChemSpider	64930
UNII	R2H3YN6E3L
KEGG	D07333
CompTox Dashboard (EPA)	DTXSID10865369
ECHA InfoCard	100.044.014
Chemical and physical data
Formula	C20H25FN4O
Molar mass	356.445 g·mol−1
3D model (JSmol)	Interactive image
SMILES Fc3ccc(N2CCN(CCC(NC(=O)c1cccnc1)C)CC2)cc3
InChI InChI=1S/C20H25FN4O/c1-16(23-20(26)17-3-2-9-22-15-17)8-10-24-11-13-25(14-12-24)19-6-4-18(21)5-7-19/h2-7,9,15-16H,8,10-14H2,1H3,(H,23,26) Key:RSKQGBFMNPDPLR-UHFFFAOYSA-N

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 (K_i = > 1 μM), and was instead found to act as a potent and selective 5-HT_2A and α₁-adrenergic receptor antagonist (K_i = 75 nM and 86 nM, respectively). ^[12] It possesses low or no affinity for the 5-HT_1A, 5-HT_2B, D₂, and β-adrenergic, as well as at SERT and VMAT (K_i = all > 1 μM), but it does have some affinity for the α₂-adrenergic receptor (K_i = 730 nM). ^[12]

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. ^[12] 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. ^[13]

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]}

References

1. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 862–. ISBN   978-1-4757-2085-3.
2. Kent A, Billiard M (2003). Sleep: physiology, investigations, and medicine. New York: Kluwer Academic/Plenum. ISBN   978-0-306-47406-4.
3. Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug Directory (Book with CD-ROM). Boca Raton: Medpharm Scientific Publishers. ISBN   978-3-88763-075-1.
4. Triggle DJ (1996). Dictionary of Pharmacological Agents. Boca Raton: Chapman & Hall/CRC. ISBN   978-0-412-46630-4.
5. Franzoni E, Masoni P, Mambelli M, Marzano P, Donati C (1987). "[Niaprazine in behavior disorders in children. Double-blind comparison with placebo]". La Pediatria Medica e Chirurgica: Medical and Surgical Pediatrics (in Italian). 9 (2): 185–7. PMID   2958783.
6. Bodiou C, Bavoux F (1988). "[Niaprazine and side effects in pediatrics. Cooperative evaluation of French centers of pharmacovigilance]". Thérapie (in French). 43 (4): 307–11. PMID   2903572.
7. Ottaviano S, Giannotti F, Cortesi F (October 1991). "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. doi:10.1007/bf00304832. PMID   1837245. S2CID   35908448.
8. Montanari G, Schiaulini P, Covre A, Steffan A, Furlanut M (1992). "Niaprazine vs chlordesmethyldiazepam in sleep disturbances in pediatric outpatients". Pharmacological Research. 25 (Suppl 1): 83–4. doi:10.1016/1043-6618(92)90551-l. PMID   1354861.
9. Younus M, Labellarte MJ (2002). "Insomnia in children: when are hypnotics indicated?". Paediatric Drugs. 4 (6): 391–403. doi:10.2165/00128072-200204060-00006. PMID   12038875. S2CID   33340367.
10. Mancini J, Thirion X, Masut A, et al. (July 2006). "Anxiolytics, hypnotics, and antidepressants dispensed to adolescents in a French region in 2002". Pharmacoepidemiology and Drug Safety. 15 (7): 494–503. doi:10.1002/pds.1258. PMID   16700077. S2CID   24273650.
11. Duchene-Marullaz P, Rispat G, Perriere JP, Hache J, Labrid C (1971). "[Some pharmacodynamical properties of niaprazine, a new antihistaminic agent]". Thérapie (in French). 26 (6): 1203–9. PMID   4401719.
12. Scherman D, Hamon M, Gozlan H, et al. (1988). "Molecular pharmacology of niaprazine". Progress in Neuro-psychopharmacology & Biological Psychiatry. 12 (6): 989–1001. doi:10.1016/0278-5846(88)90093-0. PMID   2853885. S2CID   40566589.
13. Keane PE, Strolin Benedetti M, Dow J (February 1982). "The effect of niaprazine on the turnover of 5-hydroxytryptamine in the rat brain". Neuropharmacology. 21 (2): 163–9. doi:10.1016/0028-3908(82)90157-5. PMID   6460945. S2CID   22310059.
14. Garattini S, Mennini T (1988). "Critical notes on the specificity of drugs in the study of metabolism and functions of brain monoamines". International Review of Neurobiology. 29: 259–80. doi:10.1016/s0074-7742(08)60089-6. ISBN   9780123668295. PMID   3042665.
15. USpatent 3712893,J Simond, J Moleyre, R Mauvernay, N Busch,"Butyl-piperazine derivatives",issued 1973-01-23, assigned to Centre Europeen de Recherches Mauvernay 
16. "Niaprazine". Pharmaceutical Substances. Thieme. Retrieved 2024-07-17.