Niaprazine
Encyclopedia
Niaprazine is a sedative
-hypnotic
drug
of the phenylpiperazine
class. It has been used in the treatment of sleep disturbance
s since the early 1970s in several Europe
an countries, including France
, Italy
, and Luxembourg
. It is commonly used with children and adolescents on account of its favorable safety
and tolerability
profile and lack of abuse potential.
Originally believed to act as an antihistamine
and anticholinergic
, niaprazine was later discovered to have no significant binding
affinity for either the H1
or the mACh receptor
s (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). It is virtually inactive at 5-HT1A
, 5-HT2B
, D2, and β-adrenergic, as well as at SERT
and VMAT
(Ki = all > 1 μM), but it does have some weak affinity for the α2-adrenergic receptor
(Ki = 730 nM), likely acting as an antagonist there as well.
Niaprazine has been shown to metabolize to the compound pFPP in a similar manner to how trazodone
and nefazodone
metabolize to mCPP. 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.
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
-hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
of the phenylpiperazine
Phenylpiperazine
1-Phenylpiperazine is a simple chemical compound featuring a phenyl group bound to a piperazine ring. The suffix '-piprazole' is sometimes used in the names of drugs to indicate they belong to this class....
class. It has been used in the treatment of sleep disturbance
Sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of the sleep patterns of a person or animal. Some sleep disorders are serious enough to interfere with normal physical, mental and emotional functioning...
s since the early 1970s in several Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
an countries, including France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
, Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
, and Luxembourg
Luxembourg
Luxembourg , officially the Grand Duchy of Luxembourg , is a landlocked country in western Europe, bordered by Belgium, France, and Germany. It has two principal regions: the Oesling in the North as part of the Ardennes massif, and the Gutland in the south...
. It is commonly used with children and adolescents on account of its favorable safety
Safety
Safety is the state of being "safe" , the condition of being protected against physical, social, spiritual, financial, political, emotional, occupational, psychological, educational or other types or consequences of failure, damage, error, accidents, harm or any other event which could be...
and tolerability
Tolerability
Tolerability is how tolerable in terms of side effects a medication is.As an example, tricyclic antidepressants are very poorly tolerated and often produce severe side effects including sedation, orthostatic hypotension, and anticholinergic effects, whereas the newer antidepressant agomelatine has...
profile and lack of abuse potential.
Originally believed to act as an antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
and anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
, niaprazine was later discovered to have no significant binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
affinity for either the H1
H1 receptor
The H1 receptor is a histamine receptor belonging to the family of Rhodopsin like G-protein-coupled receptors. This receptor, which is activated by the biogenic amine histamine, is expressed throughout the body, to be specific, in smooth muscles, on vascular endothelial cells, in the heart, and in...
or the mACh receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s (Ki = > 1 μM), and was instead found to act as a potent
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
and selective
Binding selectivity
Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...
5-HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
and α1-adrenergic receptor
Alpha-1 adrenergic receptor
The alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
(Ki = 75 nM and 86 nM, respectively). It is virtually inactive at 5-HT1A
5-HT1A receptor
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
, 5-HT2B
5-HT2B receptor
5-hydroxytryptamine receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.-Function:...
, D2, and β-adrenergic, as well as at SERT
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
and VMAT
Vesicular monoamine transporter
The vesicular monoamine transporter is a transport protein integrated into the membrane of intracellular vesicles of presynaptic neurons. It acts to transport monoamines into the synaptic vesicles.-Monoamines:...
(Ki = all > 1 μM), but it does have some weak affinity for the α2-adrenergic receptor
Alpha-2 adrenergic receptor
The alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
(Ki = 730 nM), likely acting as an antagonist there as well.
Niaprazine has been shown to metabolize to the compound pFPP in a similar manner to how trazodone
Trazodone
Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor class. It is a phenylpiperazine compound...
and nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
metabolize to mCPP. 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
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
activation.