Nisoxetine

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Nisoxetine
Nisoxetine.svg
Clinical data
Other namesLY-94939,
(±)-γ-(2-Methoxyphenoxy)-N-methyl-benzenepropanamine hydrochloride
ATC code
  • None
Legal status
Legal status
  • Never marketed
Identifiers
  • (RS)-3-(2-methoxyphenoxy)-N-methyl-3-phenylpropan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C17H21NO2
Molar mass 271.360 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • CNCCC(C1=CC=CC=C1)OC2=CC=CC=C2OC
  • InChI=1S/C17H21NO2/c1-18-13-12-15(14-8-4-3-5-9-14)20-17-11-7-6-10-16(17)19-2/h3-11,15,18H,12-13H2,1-2H3 Yes check.svgY
  • Key:ITJNARMNRKSWTA-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Nisoxetine, originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in humans, [1] although it was originally researched as an antidepressant. Nisoxetine is now widely used in scientific research as a standard selective norepinephrine reuptake inhibitor. [2] It has been used to research obesity and energy balance, [3] and exerts some local analgesia effects. [4]

Contents

Researchers have attempted to use a carbon-labeled form of nisoxetine for positron emission tomography (PET) imaging of the norepinephrine transporter (NET), with little success. [5] However, it seems that tritium labeled nisoxetine (3H-nisoxetine, 3H-NIS) is a useful radioligand for labeling norepinephrine uptake sites in vitro , which nisoxetine and other antagonists for NET are able to inhibit. [6]

History

In treating depression, it was theorized that substances that could enhance norepinephrine transmission, such as tricyclic antidepressants (TCA), could diminish the symptoms of clinical depression. [7] The origins of nisoxetine can be found within the discovery of fluoxetine (Prozac, by Eli Lilly). In the 1970s, Bryan B. Molloy (a medicinal chemist) and Robert Rathbun (a pharmacologist) began a collaboration to search for potential antidepressant agents that would still retain the therapeutic activity of TCAs without undesirable cardiotoxicity and anticholinergic properties. [8] [9] The antihistamine drug diphenhydramine was found to inhibit monoamine uptake in addition to antagonizing histamine receptors, and this inhibition of monoamine uptake became a potential application for treating depression. [8] [9] As a result, Molloy, along with colleagues Schmiegal and Hauser, synthesized members of the phenoxyphenylpropylamine (PPA) group as analogues of diphenhydramine. [8] [9]

Richard Kattau in the Rathbun laboratory tested the newly created drugs within the series of PPAs for their ability to reverse apomorphine-induced hypothermia in mice (PIHM), a test in which the TCAs were active antagonists. [8] [9] Kattau found that one member of the series, LY94939 (nisoxetine), was as potent and effective as the TCAs in the reversal of PIHM. [8] [9] Nisoxetine was found to be as potent as desipramine in inhibiting norepinephrine uptake in brain synaptosomes while not acting as a potent inhibitor of serotonin (5-HT) or dopamine uptake. [8] [9]

Preclinical studies in humans were also performed in 1976 to evaluate the safety and possible mechanism of nisoxetine. [10] At doses capable of blocking the uptake of norepinephrine and tyramine at nerve terminals, nisoxetine did not produce any substantial side effects. [10] Abnormal electrocardiogram effects were also not observed, indicating it to be a relatively safe compound. [10]

Later, however, researchers considered ways in which subtle chemical differences in the PPA series could selectively inhibit 5-HT uptake, which eventually led to the synthesis of nisoxetine's 4-trifluoremethyl analogue, fluoxetine. [11] Nisoxetine was never marketed as a drug due to a greater interest in pursuing the development of fluoxetine, a selective serotonin reuptake inhibitor (SSRI). [11]

Research

Obesity

Numerous evidence suggests that by altering catecholaminergic signaling (cell communication via norepinephrine and dopamine), food intake and body weight will be affected via classic hypothalamic systems that are involved in the regulation of energy balance. [3] Antidepressants, such as the atypical antidepressant bupropion, can also cause weight loss due to their ability to increase extracellular dopamine and norepinephrine by inhibiting their uptake. [3] Other research has focused on the interaction of serotonin and norepinephrine, leading to serotonin–norepinephrine reuptake inhibitors (SNRIs) as anti-obesity drugs. [3]

The primary forebrain sensor of peripheral cues that relays information about the availability of energy and storage is the arcuate nucleus of the hypothalamus (ARH), and it contains two types of cells that have opposing effects on energy balance. [3] These two types of cells are neuropeptide Y (NPY)-expressing cells, which cause hyperphagia and energy conservation, and cells that pro-opiomelanocortin (POMC), which are related to hypophagia and increased energy expenditure. [3] NPY and norepinephrine are both localized in select neurons in the brain and periphery. [3] A norepinephrine reuptake inhibitor, such as nisoxetine, could potentially cause anorexia by decreasing activity of cells that express NPY and norepinephrine. [3]

In lean and obese mice, selective and combined norepinephrine and dopamine reuptake inhibition reduces food intake and body weight. Yet selective reuptake inhibitors of norepinephrine and dopamine (nisoxetine and a substance codenamed GBR12783, respectively) independently have no effect on food intake in mice. [3] However, when given in combination, there is profound inhibition of food intake. [3] This demonstrates a synergistic interaction between dopamine and norepinephrine in controlling ingestive behavior, similar to the action of SNRIs. [3] The fact that nisoxetine alone does not affect food intake suggests that norepinephrine alone is insufficient to affect feeding or that the blocked reuptake of norepinephrine by nisoxetine is acting in the wrong place. [12] Unlike nisoxetine, its sulfur analog thionisoxetine reduces food consumption in rodents and is a more promising treatment for obesity and eating disorders. [11]

Analgesia effects

An essential activity of local anesthetics is the blockade of sodium channels. [4] In this way, local anesthetics are able to produce infiltrative cutaneous analgesia, peripheral neural blockades, as well as spinal/epidural anesthesia. [4] Due to nisoxetine's sodium channel blocking effect, it is also possible that it may also have a local anesthetic effect. [4] Nisoxetine is able to suppress the nicotine-evoked increase of hippocampal norepinephrine in a dose-dependent nature through effects on the functioning of the nicotinic acetylcholine receptors. [4] It is also able to inhibit tetrodotoxin-facilitated sensitive inward sodium currents in rat superior cervical ganglia. [4]

Nisoxetine elicits local (cutaneous) but not systemic analgesia. [4] Compared to lidocaine, a common anesthetic, nisoxetine is more potent (by four folds) and exhibits longer drug action towards producing cutaneous anesthesia. [4] NMDA receptors are not involved in this local anesthetic effect. [4] However, it is unclear whether nisoxetine may cause toxicity to the neuronal or subcutaneous tissues, which still needs to be investigated in the future. [4]

3H-nisoxetine

Due to shortcomings of the previously available radioligands for the norepinephrine uptake site, researchers needed to find a better ligand for measuring norepinephrine reuptake sites. [6] These shortcomings also meant that the norepinephrine uptake sites in the brain were less studied than the 5-HT uptake sites. [6] Previous radioligands for the norepinephrine uptake sites, 3H-desipramine (3H-DMI) and 3H-mazindol (3H-MA), did not have specific and selective binding properties for norepinephrine sites. [6]

3H-nisoxetine (3H-NIS), on the other hand, is a potent and selective inhibitor for the uptake of norepinephrine [13] and is now used as a selective marker of the norepinephrine transporter. [14] Most studies using 3H-NIS are conducted in the rat model, and not many have been performed in humans. [15] 3H-NIS can be used to map anatomical sites associated with norepinephrine uptake through the technique of quantitative autoradiography (QAR), where the pattern of 3H-NIS binding is consistent with the pattern of norepinephrine activation. [16] Lesion studies also confirm 3H-NIS's relation to presynaptic norepinephrine terminals. [16]

3H-NIS binds with high affinity (Kd = 0.7 nM) and selectivity to a homogenous population of sites that are associated with norepinephrine uptake in the rat brain. [6] Specific 3H-NIS binding increases as sodium concentration is raised, and binding of 3H-NIS is barely detectable in the absence of sodium. [6] Binding of 3H-NIS is sodium-dependent because sodium ions are necessary for the neuronal uptake of norepinephrine. [6] This binding is also heat-sensitive, where heating rat cerebral cortical membranes reduces the amount of specific binding. [6] Nisoxetine (Ki = 0.7 + 0.02 nM), as well as other compounds that have a high affinity for norepinephrine uptake sites (DMI, MAZ, maprotiline), act as potent inhibitors of 3H-NIS binding to rat cortical membranes. [6]

In humans, 3H-NIS is used to measure uptake sites in the locus coeruleus (LC). The LC, a source of norepinephrine axons, has been of focus in research due to reports of cell loss in the area that occurs with aging in humans. [17] Decreased binding of 3H-NIS reflects the loss of LC cells. [17]

NET imaging using PET

Researchers are attempting to image the norepinephrine transporter (NET) system using positron emission tomography (PET). Possible ligands to be used for this methodology must possess high affinity and selectivity, high brain penetration, appropriate lipophilicity, reasonable stability in plasma, as well as high plasma free fraction. [18] 11C-labeled nisoxetine, synthesized by Haka and Kilbourn, was one possible candidate that was investigated for being used as a potential PET tracer. [5] [6] However, in vivo, 11C-labeled nisoxetine exhibits nonspecific binding, therefore limiting its effectiveness as a possible ligand for PET. [6]

Pharmacological properties

Nisoxetine is a potent and selective inhibitor of norepinephrine uptake, where it is about 1000-fold more potent in blocking norepinephrine uptake than that of serotonin. [19] It is 400-fold more potent in blocking the uptake of norepinephrine than that of dopamine. The R-isomer of nisoxetine has 20 times greater affinity than its S-isomer for NET. Nisoxetine has little or no affinity for neurotransmitter receptors. [19] The NET Ki for nisoxetine is generally agreed to be 0.8 nM. [11]

In a preclinical study where nisoxetine was administered to volunteers, the average plasma concentration after a single dose was found to be 0.028 microgram/ml, and after the fifteenth dose was 0.049 microgram/ml. [10] The binding of nisoxetine is saturable in human placental NET, with specific binding values being 13.8 + 0.4 nM for Kd and 5.1 + 0.1 pmol/mg of protein for Bmax [15] Sodium and chloride enhances nisoxetine binding by increasing the affinity of the binding site for its ligand, where Kd values increase as the concentration of chloride decrease. [15] Bmax is not affected. [15]

Activity of 3H-NIS on cerebral cortical homogenates in mice show a Kd of 0.80 + 0.11 nM and a Bmax of + 12 fmol/mg protein. [6] Density of binding is generally associated with brain regions that exhibit norepinephrine levels, where the highest specific 3H-NIS binding is in the brainstem (LC) and the thalamus. [16] [18] Specific 3H-NIS binding is dependent on sodium cations, where specific and total binding is raised as the concentration of sodium is increased (Tejani-Butt et al., 1990). This binding occurs with high affinity towards a single class of sites that have similar pharmacological characteristics of the norepinephrine uptake site. [6]

Nisoxetine and other inhibitors of norepinephrine uptake sites are able to inhibit the binding of 3H-NIS. When rats are intravenously injected with nisoxetine and the binding of 3H-NIS is measured, the Ki of nisoxetine is reported to be 0.8 + 0.1 nM for concentrations of up to 1 μM. [16]

Adverse effects

Norepinephrine, along with dopamine and/or other serotonin reuptake inhibitors, are often prescribed in the treatment of mood disorders and are generally well tolerated.

Preclinical studies in humans using nisoxetine were conducted in the 1970s, and side effects of the drug were examined. [10] Doses ranging from 1 mg to 50 mg do not result in any changes in base line values in haematologic tests, routine blood chemistries, or coagulation parameters. [10] Larger doses produce some side effects, but no electrocardiographic changes are observed in any doses. [10] Injections with doses of tyramine in humans while receiving nisoxetine results in a decreased responsiveness to tyramine with increased duration of administered nisoxetine. [10] Another effect of nisoxetine administration is that subjects require much smaller doses of norepinephrine to produce the same blood pressure responses as those who receive a placebo. [10] In other words, subjects exhibit an increased sensitivity to norepinephrine after nisoxetine administration. [10] Preclinical test conclude that the drug, in tested doses, appears to be safe for use in humans. [10]

Chemical properties

Nisoxetine is a racemic compound with two isomers.

Tricyclic (three-ring) structures can be found in many different drugs, and for medicinal chemists allows restrictions for the conformational mobility of two phenyl rings attached to a common carbon or hetero (non-carbon) atom. [11] Small molecular changes, such as substituents or ring flexibility can cause changes in the pharmacological and physiochemical properties of a drug. [11] The mechanism of action for the phenoxyphenylpropyamines can be explained by the critical role of the type and position of the ring substitution. [11] The unsubstituted molecule is a weak SSRI. [11] A compound highly potent and selective for blocking norepinephrine reuptake, a SNRI, results from 2-substitutions into the phenoxy ring. [11]

See also

Related Research Articles

Tricyclic antidepressant Class of medications

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

Reuptake

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

Monoamine transporter

Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and posttranslational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

Serotonin–norepinephrine reuptake inhibitor Class of antidepressant medication

Serotonin–noradrenaline reuptake inhibitors (SNRIs) are a class of antidepressant drugs that treat major depressive disorder (MDD), anxiety disorders, obsessive–compulsive disorder (OCD), social phobia, attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and noradrenaline. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act upon serotonin only.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

Trimipramine Antidepressant

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

Norepinephrine transporter Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

Fluoxetine SSRI Antidepressant

Fluoxetine, sold under the brand names Prozac and Sarafem among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder. It is also approved for treatment of major depressive disorder in adolescents and children 8 years of age and over. It has also been used to treat premature ejaculation. Fluoxetine is taken by mouth.

Phenyltropane

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these analogues. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

(+)-CPCA Stimulant drug

(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission.

Reuptake inhibitor Type of drug

A reuptake inhibitor (RI) is a type of drug known as a reuptake modulator that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

Oxaprotiline Chemical compound

Oxaprotiline, also known as hydroxymaprotiline, is a norepinephrine reuptake inhibitor of the tetracyclic antidepressant (TeCA) family that is related to maprotiline. Though investigated as an antidepressant, it was never marketed.

Monoamine releasing agent Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective DRAs are currently known. Many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known, however. Serotonin–dopamine releasing agents are much rarer and are not selective for monoamine release. Examples of NDRAs include amphetamine and methamphetamine, and an example of an SNDRA is MDMA. The most selective dopamine releaser is 4-methylaminorex, but it also has considerable activity as a norepinephrine releaser. These drugs are frequently used for recreational purposes and encountered as drugs of abuse.

JNJ-7925476 Chemical compound

JNJ-7925476 is a triple reuptake inhibitor antidepressant discovered by Johnson & Johnson, but never marketed.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

Decynium-22 Cationic derivative of quinoline

Decynium-22 is a cationic derivative of quinoline, and a potent inhibitor of the plasma membrane monoamine transporter (PMAT), as well as all members of the organic cation transporter (OCT) family in both human and rat cells. However, it has little effect on high affinity monoamine transporters such as the dopamine transporter and norepinephrine transporter.

Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have contributed to the major advances as antidepressants where they have revolutionised the treatment of depression and other psychiatric disorders. The SSRIs are therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD) and anorexia. There is also clinical evidence of SSRIs efficiency in the treatment of the negative symptoms of schizophrenia and their ability to prevent cardiovascular diseases.

Selective norepinephrine reuptake inhibitors (sNRIs) are a class of drugs that have been marketed as antidepressants and are used for various mental disorders, mainly depression and attention-deficit hyperactivity disorder (ADHD). The norepinephrine transporter (NET) serves as the fundamental mechanism for the inactivation of noradrenergic signaling because of the NET termination in the reuptake of norepinephrine (NE). The selectivity and mechanism of action for the NRI drugs remain mostly unresolved and, to date, only a limited number of NRI-selective inhibitors are available. The first commercially available selective NRI was the drug reboxetine (Edronax), developed as a first-line therapy for major depressive disorder. Atomoxetine (Strattera) is another potent and selective NRI which is also effective and well tolerated for the treatment of ADHD in adults; it may also be a new treatment option for adults with ADHD, particularly for those patients at risk of substance abuse.

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