Serotonin–norepinephrine–dopamine reuptake inhibitor
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A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of
Other SNDRIs were developed as potential
The SNDRIs are similar to non-selective
Although their primary mechanisms of action are as NMDA receptor antagonists, ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse.
Indications
Depression
About 16% of the population is estimated to be affected by major depression, and another 1% is affected by bipolar disorder, one or more times throughout an individual's lifetime. The presence of the common symptoms of these disorders are collectively called 'depressive syndrome' and includes a long-lasting
Major depression can strike at virtually any time of life as a function of genetic and developmental pre-disposition in interaction with adverse life-events. Although common in the elderly, over the course of the last century, the average age for a first episode has fallen to ~30 years. However, depressive states (with subtly different characteristics) are now frequently identified in adolescents and even children. The differential diagnosis (and management) of depression in young populations requires considerable care and experience; for example, apparent depression in teenagers may later transpire to represent a
The ability to work, familial relationships, social integration, and self-care are all severely disrupted.[6]
The genetic contribution has been estimated as 40-50%. However, combinations of multiple genetic factors may be involved because a defect in a single gene usually fails to induce the multifaceted symptoms of depression.[12]
Pharmacotherapy
There remains a need for more efficacious antidepressant agents. Although two-thirds of patients will ultimately respond to antidepressant treatment, one-third of patients respond to placebo,[20] and remission is frequently sub-maximal (residual symptoms). In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy (tachyphylaxis). Also, currently available antidepressants all elicit undesirable side-effects, and new agents should be divested of the distressing side-effects of both first and second-generation antidepressants.[6]
Another serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, in general one must reckon with a delay of 3–6 weeks before full efficacy is attained. In general, this delay to onset of action is attributed to a spectrum of long-term adaptive changes. These include receptor desensitization, alterations in intracellular transduction cascades and gene expression, the induction of neurogenesis, and modifications in synaptic architecture and signaling.[6]
Depression has been associated with impaired
DA may promote
Dense connections exist between monoaminergic neurons. Dopaminergic neurotransmission regulates the activity of 5-HT and NE in the dorsal raphe nucleus (DR) and locus coeruleus (LC), respectively. In turn, the ventral tegmental area (VTA) is sensitive to 5-HT and NE release.[3]
In the case of SSRIs, the promiscuity among transporters means that there may be more than a single type of neurotransmitter to consider (e.g. 5-HT, DA, NE, etc.) as mediating the therapeutic actions of a given medication. MATs are able to transport monoamines other than their "native" neurotransmitter. It was advised to consider the role of the
To examine the role of
The
Most common CNS disorders are highly
Clozapine is an example of a drug used in the treatment of certain CNS disorders, such as schizophrenia, that has superior efficacy precisely because of its broad-spectrum mode of action. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious.[23][24][25][26][27][28][29][30]
In addition, the nonselective MAOIs and the TCA SNRIs are widely believed to have an efficacy that is superior to the SSRIs normally picked as the first-line choice of agents for/in the treatment of MDD and related disorders.
Applications other than depression
- Cocaine addiction (e.g., indatraline)[34]
- Obesity (e.g., amitifadine, tesofensine)[35]
- EB-1020)[36]
- Chronic pain (c.f. bicifadine)[37]
- Parkinson's disease
List of SNDRIs
Approved pharmaceuticals
- Mazindol (Mazanor, Sanorex) – anorectic; ki is 50 nM for SERT, 18 nM for NET, 45 nM for DAT[38]
- Nefazodone (Serzone, Nefadar, Dutonin) – antidepressant; non-selective; ki is 200 nM at SERT, 360 nM at NET, 360 nM at DAT
- Nefopam (ki SER/NE/DA = 29/33/531 nM) Informative review:[39]
Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI in vitro with ki values of 298 nM at SERT, 5451 at NET, 943 nM at DAT.[38] However, it appears to act as a prodrug in vivo to metabolites that are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and in accordance, sibutramine behaves contrarily as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake (16%).[40][41][1]
Venlafaxine (Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced with ki values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93.[42] It may weakly inhibit the reuptake of dopamine at high doses.[43]
Coincidental
- abuse potential
- abuse potential
- psychostimulant drug of abuse; SNDRI action likely contributes to effects and abuse potential[44]
- Tripelennamine (Pyribenzamine) – antihistamine; weak SNDRI; sometimes abused for this reason[45][46][47][48]
- Mepiprazole
Undergoing clinical trials
- Ansofaxine (LY03005/LPM570065).[49] Completed Phase 2 & 3 trials. FDA accepted NDA application.[50]
- Centanafadine (EB-1020) – see here for details Archived 2012-05-31 at the Wayback Machine 1 to 6 to 14 ratio for NDS. Completed Phase 3 trials for ADHD.[51]
- OPC-64005 - In phase 2 trials (2022)[52]
- Lu AA37096 – see here (SNDRI and 5-HT6 modulator)
- NS-2360 – principle metabolite of tesofensine
- Tesofensine (NS-2330) (2001) In trials for obesity.[53]
Failed clinical trials
- Bicifadine (DOV-220,075) (1981)[54][55]
- BMS-866,949
- Brasofensine (NS-2214, BMS-204,756) (1995)[56]
- Diclofensine (Ro 8–4650) (1982)[57][58]
- DOV-216,303 (2004)[59][60]
- EXP-561 (1965)[61]
- Liafensine (BMS-820,836)
- NS-2359 (GSK-372,475)[62]
- RG-7166 (2009–2012)
- SEP-227,162
- SEP-228,425
- SEP-432 aka SEP-228432, CID:58954867
- Amitifadine (DOV-21,947, EB-1010) (2003)[63]
- Dasotraline (SEP-225,289)[64]
- Lu AA34893 – see here[permanent dead link] (SNDRI and 5-HT2A, α1, and 5-HT6 modulator)[65]
- Tedatioxetine (Lu AA24530) – SNDRI and 5-HT2C, 5-HT3, 5-HT2A, and α1 modulator[66][67][68]
Designer drugs
Research compounds (no record of having been taken by humans)
- 3,4-Diphenylquinuclidine HCl salt: [72811-36-0].[73]
- 3,4-Diphenylpiperidines (a panoply of analogs was disclosed by French Hoechst) Ref:[74][75] Patents:[76][77] The 3',4'-Dichloro lactam was the most powerful psychostimulant tested. Its SAR can be compared to a similar French Hoechst compound called Lomevactone.
- MDL 47,832 [52423-89-9][78] Patent:[79][80] SAR is similar to RG-7166 & Amitifadine. For SAR study see under Osanetant.
- 3,3-Diphenylcyclobutanamine (1978)[81]
- AK Dutta: D-161 (2008)[82] D-473 [1632000-05-5] & D-578. Informative review:[83]
- DOV-102,677 (2006–2011)[32] Informative reviews:[84][85]
- Fezolamine (Win-41,528-2)
- HP-505[89]
- Lundbeck group: Indatraline (1985),[90] Lu-AA42202 & CID:11515108 [874296-10-3].[91]
- JNJ-7925476 (2008; first appeared in 1987),[92] Mcn 5707 [96795-88-9] & Mcn-5292 [105234-89-7].
- Kozikowski group: DMNPC (2000),[93] JZ-IV-10 (2005)[94] & JZAD-IV-22 (2010)[95]
- Lilly group: LR-5182 (maybe only NDRI) (1978) CID:9903806:[96]
- HM Deutsch group: Methylnaphthidate (HDMP-28) (2001)[100]
- NMDA antagonist.
- Benzazepine derivatives: SKF-83,959 (2013)[105] & Nor-Trepipam [20569-49-7]:[106]
- Various
- NeuroSearch group: NS9775,[108] NS18283.[109] & 4-Benzhydryl-1,2,3,6-tetrahydropyridine [1186529-81-6].
- CID:54673194 (ki S/N/D = 0.26/6.0/4.8 nM)[110]
- CID:9921901 [387869-25-2],[111] 3-(3,4-Dichlorophenyl)-tropan-2-ene (S/N/D = 4.7/26/79 nM)[112]
- Liming Shao (Sepracor/Sunovion). 3’,4’-Dichlorotramadol,[113] CID:53321058 (S/N/D = 19/04/01 nM).[114][115]
- A patent review was also disclosed:[116]
- CID:66809062:[117][118] CID:46870521[119] CID:10151573[120] CID:46701015[121]
- Takeda group, CID:44629033 (ki S/N/D = 11/14/190 nM) Ref:[122] Patent:[123]
- Trudell group: HK3-263 (ki S/N/D = 0.3/20/16 nM):[124]
- Pfizer group CP-607366 & CP-939689.
- Desmethylsertraline – active metabolite of sertraline; ki is 76 nM for SERT, 420 nM for NET, 440 nM for DAT[125]
- 3,4-Dichlorotametraline (trans-(1R,4S)-sertraline) (1980)[126]
- Venlafaxine analogues, LPM580098[127] & LPM580153.[128] And TP1[129] later reassigned name to PA01.[130]
- PRC (Carlier) group:
- Albany Molecular Research group (Bruce Molino) AMR-2 (ki is DAT 3.1 nM, SERT 8.3 nM, NET 3.0 nM):[133]
- CID:49765424 (S)-enantiomer: [1254941-82-6]:[134]
- SK Group: SKL-10406 CID:44555333[135] & CID:49866033[136][137]
- Boots UK: BTS 74,398, SPD-473citrate: [161190-26-7]
- Pridefine
- SMe1EC2M3[138]
- SIPI5357 (CID:52939791):[139]
- 23j-S (ki S/N/D = 83/3.8/160 nM):[140]
- Tetrazoles (ROK):[141][142][143]
- 10dl (CID:118713802) (ki S/N/D 7.6/45.2/330 nM):[144]
- 2at (CID:118706539):[145]
- THIQ Derivatives: AN12 (CID:10380161):[146] Patent:[147] CID:9839278:[148]
- 2j (CID:66572162) (ki S/N/D = 411/71/159 nM):[149]
- 6aq (CID:70676472) (ki S/N/D 44/10/32 nM):[150]
- Naphthyl milnacipran analog (2007), CID:17748230 (ki S/N/D = 18/05/140 nM).[151]
Herbals
- The drug of abuse
- Ginkgo biloba extract (EGb761) – "The norepinephrine (NET), the serotonin (SERT), the dopamine (DAT) uptake transporters and MAO activity are inhibited by EGb761 in vitro"[152]
- over-the-counterherbal antidepressant
- Hyperforin
- Adhyperforin
- Uliginosin B – IC50 DA = 90 nM, 5-HT = 252 nM, NE = 280 nM[153][154]
- Oregano extract.[155]
- Although not specifically a SNDRI, Rosmarinus officinalis is one of the trimonoamine modulator (TMM) that affect SER/CAs.[156]
- Hederagenin:[157]
Toxicological
). In the case of the phenyltropanes, although there are four chiral carbons, there are only eight possible isomers to consider. This is based on the fact that the compound is bicyclic and therefore does not adhere to the equation given above.It is complicated to explain which
In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased appetite (and hence weight loss), increased locomotor activity (LMA) etc. In the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose.[168] People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. On removal of the 2C tropane bridge and on going from RTI-31 to the simpler SS and RS Nocaine it was seen that these compounds still possessed activity as NDRIs but were not powerful psychostimulants. Hence, this might be viewed as a strategy for increasing the safety of the compounds and would also be preferable to use in patients who are not looking to achieve weight loss.
In light of the above paragraph, another way of reducing the psychomotor stimulant and addictive qualities of phenyltropane stimulants is in picking one that is relatively serotonergic. This strategy was employed with success for RTI-112.[107][169][170]
Another thing that is important and should be mentioned is the risk for serotonin syndrome when incorporating the element of 5-HT transporter inhibition into a compound that is already fully active as a NDRI (or vice versa). The reasons for serotonin syndrome are complicated and not fully understood.
Addiction
Drug addiction may be regarded as a disease of the brain reward system. This system, closely related to the system of emotional arousal, is located predominantly in the
There are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behavior.[171][172][173]
According to various studies, the relative likelihood of rodents and non-human primates self-administering various psychostimulants that modulate monoaminergic neurotransmission is lessened as the dopaminergic compounds become more serotonergic.
The above finding has been found for amphetamine and some of its variously substituted analogs including
RTI-112 is another good example of the compound becoming less likely to be self-administered by the test subject in the case of a dopaminergic compound that also has a marked affinity for the serotonin transporter.[169]
Further evidence that 5-HT dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with SSRIs,[177] and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.[178]
NET blockade is unlikely to play a major role in mediating addictive behavior. This finding is based on the premise that desipramine is not self-administered,[179] and also the fact that the NRI atomoxetine was not reinforcing.[180] However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC.
Relation to cocaine
Cocaine is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors. Cocaine is a relatively "balanced" inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. In addition, cocaine has some serious limitations in terms of its cardiotoxicity[181] due to its local anesthetic activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health.
Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their
... limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness.[182]
However, not all SNDRIs are reliably self-administered by animals. Examples include:
- PRC200-SS was not reliably self-administered.[131]
- RTI-112 was not self-administered[169] because at low doses the compound preferentially occupies the SERT and not the DAT.[107][170]
- addicts.[183]
- The nocaine analog JZAD-IV-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction.[95]
Legality
Cocaine is a controlled drug (Class A in the UK; Schedule II in the USA); it has not been entirely outlawed in most countries, as despite having some "abuse potential" it is recognized that it does have medical uses.
Brasofensine was made "class A" in the UK under the MDA (misuse of drugs act). The semi-synthetic procedure for making BF uses cocaine as the starting material.
Naphyrone first appeared in 2006 as one of quite a large number of analogs of pyrovalerone designed by the well-known medicinal chemist P. Meltzer et al.[70] When the designer drugs mephedrone and methylone became banned in the United Kingdom, vendors of these chemicals needed to find a suitable replacement. Mephedrone and methylone affect the same chemicals in the brain as a SNDRI, although they are thought to act as monoamine releasers and not act through the reuptake inhibitor mechanism of activity.[184] A short time later, mephedrone and methylone were banned (which had become quite popular by the time they were illegalized), naphyrone appeared under the trade name NRG-1.[71] NRG-1 was promptly illegalized, although it is not known if its use resulted in any hospitalizations or deaths.
Role of monoamine neurotransmitters
Monoamine hypothesis
The original monoamine hypothesis postulates that depression is caused by a deficiency or imbalances in the monoamine neurotransmitters (5-HT, NE, and DA). This has been the central topic of depression research for approximately the last 50 years;[12][185] it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways.[186]
When reserpine (an alkaloid with uses in the treatment of hypertension and psychosis) was first introduced to the West from India in 1953, the drug was unexpectedly shown to produce depression-like symptoms. Further testing was able to reveal that reserpine causes a depletion of monoamine concentrations in the brain. Reserpine's effect on monoamine concentrations results from blockade of the vesicular monoamine transporter, leading to their increased catabolism by monoamine oxidase. However, not everyone has been convinced by claims that reserpine is depressogenic, some authors (David Healy in particular) have even claimed that it is antidepressant.[187]
Tetrabenazine, a similar agent to reserpine, which also depletes catecholamine stores, and to a lesser degree 5-HT, was shown to induce depression in many patients.[188][189]
Iproniazid, an inhibitor of MAO, was noted to elevate mood in depressed patients in the early 1950s, and soon thereafter was shown to lead to an increase in NA and 5-HT.[185][189]
Hertting et al. demonstrated that the first TCA, imipramine, inhibited cellular uptake of NA in peripheral tissues. Moreover, both antidepressant agents were demonstrated to prevent reserpine-induced sedation. Likewise, administration of DOPA to laboratory animals was shown to reverse reserpine induced sedation; a finding reproduced in humans. Amphetamine, which releases NA from vesicles and prevents re-uptake was also used in the treatment of depression at the time with varying success.[189]
In 1965 Schildkraut formulated the
Shortly after Schildkraut's catecholamine hypothesis was published, Coppen proposed that 5-HT, rather than NA, was the more important neurotransmitter in depression. This was based on similar evidence to that which produced the NA theory as reserpine, imipramine, and iproniazid affect the 5-HT system, in addition to the noradrenergic system. It was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-HT neurotransmission remained unaltered there was no sedation in animals. Alongside this, the main observation promoting the 5-HT theory was that administration of a MAOI in conjunction with tryptophan (precursor of 5-HT) elevated mood in control patients and potentiated the antidepressant effect of MAOI. Set against this, combination of an MAOI with DOPA did not produce a therapeutic benefit.[189]
Inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more SERT selective than the parent compound.[185]
Clomipramine was a predecessor to the development of the more recent SSRIs. There was, in fact, a time prior to the SSRIs when selective NRIs were being considered (c.f. talopram and melitracen). In fact, it is also believed that the selective NRI nisoxetine was discovered prior to the invention of fluoxetine.[192] However, the selective NRIs did not get promoted in the same way as did the SSRIs, possibly due to an increased risk of suicide. This was accounted for on the basis of the energizing effect that these agents have.[193] Moreover, NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs.[194] Nevertheless, NRIs have still found uses.
Further support for the monoamine hypothesis came from monoamine depletion studies:
- Alpha-methyl-p-tyrosine (AMPT) is a tyrosine hydroxylase enzyme inhibitor that serves to inhibit catecholamine synthesis. AMPT led to a resurgence of depressive symptoms in patients improved by the NE reuptake inhibitor (NRI) desipramine, but not by the SSRI fluoxetine.[195]The mood changes induced by AMPT may be mediated by decreases in norepinephrine, while changes in selective attention and motivation may be mediated by dopamine.
- Dietary depletion of the DA precursors phenylalanine and tyrosine does not result in the relapse of formerly depressed patients off their medication.[196]
- Administration of fenclonine (para-chlorophenylalanine) is able to bring about a depletion of 5-HT. The mechanism of action for this is via tryptophan hydroxylase inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients,[197] but it is considered too toxic for use today.
- Although depletion of tryptophan — the rate-limiting factor of serotonin synthesis — does not influence the mood of healthy volunteers and untreated patients with depression, it does produce a rapid relapse of depressive symptoms in about 50% of remitted patients who are being, or have recently been treated with serotonin selective antidepressants.[198]
Dopaminergic
There appears to be a pattern of symptoms that are currently inadequately addressed by serotonergic antidepressants – loss of pleasure (anhedonia), reduced motivation, loss of interest, fatigue and loss of energy, motor retardation, apathy and hypersomnia. Addition of a pro-dopaminergic component into a serotonin based therapy would be expected to address some of these short-comings.[199][200][201]
Several lines of evidence suggest that an attenuated function of the dopaminergic system may play an important role in depression:
- Mood disorders are highly prevalent in pathologies characterized by a deficit in central DA transmission such as Parkinson's disease (PD). The prevalence of depression can reach up to 50% of individuals with PD.[202]
- Patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to develop symptoms of depression.[203]
- Data from clinical studies have shown that DA agonists, such as bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties.[10]
- Amineptine, a TCA-derivative that predominantly inhibits DA re-uptake and has minimal noradrenergic and serotonergic activity has also been shown to possess antidepressant activity. A number of studies have suggested that amineptine has similar efficacy to the TCAs, MAOIs and SSRIs. However, amineptine is no longer available as a treatment for depression due to reports of an abuse potential.
- The B-subtype selective Emsam). For some reason, there have been numerous reports of users taking this drug in conjunction with β-phenethylamine.
- Taking psychostimulants for the alleviation of depression is well proven strategy, although in a clinical setting the use of such drugs is usually prohibited because of their strong addiction propensity.[204][205]
- When users withdraw from psychostimulant drugs of abuse (in particular, amphetamine), they experience symptoms of depression. This is likely because the brain enters into a hypodopaminergic state, although there might be a role for noradrenaline also.
For these drugs to be reinforcing, they must block more than 50% of the DAT within a relatively short time period (<15 minutes from administration) and clear the brain rapidly to enable fast repeated administration.
In addition to mood, they may also improve cognitive performance,[206] although this remains to be demonstrated in humans.
The rate of clearance from the body is faster for ritalin than it is for regular amphetamine.
Noradrenergic
The decreased levels of NA proposed by Schildkraut, suggested that there would be a compensatory upregulation of β-adrenoceptors. Despite inconsistent findings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ECT) decrease β-adrenoceptor density in the rat forebrain. This led to the theory that β-adrenoceptor downregulation was required for clinical antidepressant efficacy. However, some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density.[189]
Another adrenoceptor implicated in depression is the presynaptic α2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of α2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of α2-adrenoceptor activity) although platelet studies proved inconsistent. This supersensitivity of α2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression.
In addition to enhancing NA release, α2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of α2-adrenoceptors present on 5-HT nerve terminals.
Serotonergic
5-Hydroxytryptamine (5-HT or serotonin) is an important cell-to-cell signaling molecule found in all animal phyla. In mammals, substantial concentrations of 5-HT are present in the central and peripheral nervous systems, gastrointestinal tract and cardiovascular system. 5-HT is capable of exerting a wide variety of biological effects by interacting with specific membrane-bound receptors, and at least 13 distinct 5-HT receptor subtypes have been cloned and characterized. With the exception of the 5-HT3 receptor subtype, which is a transmitter-gated ion channel, 5-HT receptors are members of the 7-transmembrane G protein-coupled receptor superfamily. In humans, the serotonergic system is implicated in various physiological processes such as sleep-wake cycles, maintenance of mood, control of food intake and regulation of blood pressure. In accordance with this, drugs that affect 5-HT-containing cells or 5-HT receptors are effective treatments for numerous indications, including depression, anxiety, obesity, nausea, and migraine.
Because serotonin and the related hormone melatonin are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. This is accounted for by the lethargic feel that some SSRIs can produce, although TCAs and antipsychotics can also cause lethargy albeit through different mechanisms.
Appetite suppression is related to 5-HT2C receptor activation as for example was reported for PAL-287 recently.
Activation of the 5-HT2C receptor has been described as "panicogen" by users of ligands for this receptor (e.g., mCPP). Antagonism of the 5-HT2C receptor is known to augment dopaminergic output. Although SSRIs with 5-HT2C antagonist actions were recommended for the treatment of depression, 5-HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless, the 5-HT2C is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonized.
Azapirone-type drugs (e.g., buspirone), which act as 5-HT1A receptor agonists and partial agonists have been developed as anxiolytic agents that are not associated with the dependence and side-effect profile of the benzodiazepines. The hippocampal neurogenesis produced by various types of antidepressants, likewise, is thought to be mediated by 5-HT1A receptors.[citation needed] Systemic administration of a 5-HT1A agonist also induces growth hormone and adrenocorticotropic hormone (ACTH) release through actions in the hypothalamus.[208]
Current antidepressants
Most antidepressants on the market today target the monoaminergic system.
SSRIs
The most commonly prescribed class of antidepressants in the USA today are the selective serotonin reuptake inhibitors (SSRIs). These drugs inhibit the uptake of the neurotransmitter 5-HT by blocking the SERT, thus increasing its synaptic concentration, and have shown to be efficacious in the treatment of depression, however sexual dysfunction and weight gain are two very common side-effects that result in discontinuation of treatment.
Although many patients benefit from SSRIs, it is estimated that approximately 50% of depressive individuals do not respond adequately to these agents.[209] Even in remitters, a relapse is often observed following drug discontinuation. The major limitation of SSRIs concerns their delay of action. It appears that the clinical efficacy of SSRIs becomes evident only after a few weeks.[210]
SSRIs can be combined with a host of other drugs including bupropion, α2 adrenergic antagonists (e.g., yohimbine) as well as some of the atypical antipsychotics. The augmentation agents are said to behave synergistically with the SSRI although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. It is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. In addition, single compounds are more likely to be approved by the FDA than are drugs that contain greater than one pharmaceutical ingredient (polytherapies).
A number of SRIs were under development that had auxiliary interactions with other receptors. Particularly notable were agents behaving as co-joint SSRIs with additional antagonist activity at 5-HT1A receptors. 5-HT1A receptors are located presynaptically as well as post-synaptically. It is the presynaptic receptors that are believed to function as
NRIs
NDRIs
SNRIs
Serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor), its active metabolite desvenlafaxine (Pristiq), and duloxetine (Cymbalta) prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the SSRIs.[211]
Sibutramine is the name of an SNRI based appetite suppressant with use in the treatment of obesity. This was explored in the treatment of depression, but was shown not to be effective.
Both sibutramine and venlafaxine are phenethylamine-based. At high doses, both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA reuptake is unlikely to be relevant at clinically approved doses.
MAOIs
The MAOIs work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. The fact that they are more efficacious than the newer generation antidepressants[citation needed] is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters.[citation needed] The problem with MAOIs is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. Although selective MAOIs can reduce, if not eliminate these risks, their efficacy tends to be lower.
MAOIs may preferentially treat TCA-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. This may be a function of the ability of MAOIs to increase synaptic levels of DA in addition to 5-HT and NE. The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia (FM) or chronic fatigue syndrome (CFS).
Although a substantial number of MAOIs were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. The reason for this is that they were
TCAs
The first
The TCAs such as imipramine and amitriptyline typically prevent the reuptake of serotonin or norepinephine.
It is the histaminiergic (H1), muscarinic acetylcholinergic (M1), and alpha adrenergic (α1) blockade that is responsible for the side-effects of TCAs. These include somnolence and lethargy, anticholinergic side-effects, and hypotension. Due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the TCAs could be lethal. TCAs were, for 25 years, the leading cause of death from overdoses in many countries. Patients being treated with antidepressants are prone to attempt suicide and one method they use is to take an overdose of their medications.[213]
Another example of a TCA is amineptine which is the only one believed to function as a DRI. It is no longer available.
Failure of SNDRIs for depression
SNDRIs have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in
See also
- List of antidepressants
- Selective serotonin reuptake inhibitor (SSRI)
- Serotonin–norepinephrine reuptake inhibitor (SNRI)
- Monoamine reuptake inhibitor (MRI)
References
- PMID 19110199.
- S2CID 71382550.
- ^ PMID 19702555.
- ^ PMID 19587855.
- S2CID 20271918.
- ^ PMID 16522330.
- ^ PMID 18690111.
- ^ PMID 18311656.
- PMID 20856599.
- ^ PMID 19501541.
- ^ "Depression". World Health Organization. WHO. Archived from the original on 2010-07-17.
- ^ PMID 20219105.
- S2CID 24986156.
- ^ PMID 19748369.
- S2CID 32439196.
- PMID 22412144.
- S2CID 11532256.
- PMID 19945804.
- PMID 22516274.
- S2CID 33347610.
- S2CID 26550661.
- PMID 19022290.
- ^ PMID 20704963.
- S2CID 20913769.
- PMID 19110195.
- S2CID 11395584.
- S2CID 4414021.
- S2CID 4362713.
- PMID 16442279.
- PMID 18936753.
- PMID 16001091.
- ^ PMID 22150508.
- PMID 17908267.
- S2CID 20465584.
- S2CID 12020136.
- ^ "Efficacy and Safety of NS2359 in Adults with Attention Deficit Hyperactivity Disorder. A Randomised, Double-Blind, Placebo-Controlled Study". ClinicalTrials.gov. 27 April 2007.
- S2CID 17215882.
- ^ ISBN 978-1-84973-365-6.
- PMID 28731336.
- S2CID 24789264.
- ISBN 978-0-415-30321-7.
- ISBN 978-1-118-67846-6.
- S2CID 26795121.
- PMID 24251803.
- S2CID 20653998.
- PMID 8791174.
- S2CID 16399789.
- ISBN 978-0-8147-3669-2.
- PMID 24614602.
- ^ "NDA Filing for Luye Pharma's Antidepressant Drug LY03005 Accepted by the U.S. FDA - Press Releases - Luye Pharma Group". www.luye.cn. Retrieved 2022-06-11.
- ^ "A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel-group Trial Evaluating the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release Tablets in Adults With Attention-deficit/Hyperactivity Disorder". ClinicalTrials.gov. 2021-09-20.
- ^ "OPC 64005 - AdisInsight". adisinsight.springer.com. Retrieved 2022-12-19.
- ^ "Tesofensine - Saniona - AdisInsight". adisinsight.springer.com. Retrieved 2022-06-11.
- PMID 7241504.
- PMID 16898842.
- ^ a b EP 0756596, Moldi, Peter; Watjen, Frank & Scheel-Krueger, Jorgen, "Tropane-2-aldoxine derivatives as neurotransmitter reuptake inhibitors", published 1997-02-05, assigned to Neurosearch AS
- PMID 6979165.
- PMID 7107085.
- S2CID 26944976.
- S2CID 20809504.
- ^ U.S. patent 3,308,160PHENYLBICYCLO[Z.Z.Z]OCTANE-L-AMINES AND SALTS THEREOF.
- S2CID 9365152.
- ^ "EUTHYMICS REPORTS TOP-LINE RESULTS FROM TRIADE TRIAL OF AMITIFADINE FOR MAJOR DEPRESSIVE DISORDER" (PDF) (Press release). Euthymics Bioscience, Inc. May 29, 2013. Archived from the original (PDF) on 2017-09-24. Retrieved 2022-06-11.
- ^ "Sunovion Discontinues Dasotraline Program". www.businesswire.com. 2020-05-13. Retrieved 2022-06-11.
- ^ "Efficacy and Safety of Lu AA34893 in Patients With Major Depressive Disorder". ClinicalTrials.gov. 2010-09-28.
- ^ "Development programme - Lundbeck". Archived from the original on 2011-09-29. Retrieved 2012-04-18.
- ^ "Search of: Lu AA24530 - List Results". ClinicalTrials.gov.
- ^ "Tedatioxetine - AdisInsight". adisinsight.springer.com. Retrieved 2022-06-11.
- PMID 30105474.
- ^ PMID 16480278.
- ^ a b Alan Travis (2010-04-01). "NRG-1 may be next legal high to face ban by ministers | Politics". The Guardian. Retrieved 2010-04-03.
- S2CID 5108266.
- ^ Claude G. A. Gueremy, et al. U.S. patent 4,224,332 (1980 to Pharmindustrie).
- .
- .
- ^ Jacques Dreux & Serge Petit, US4785007 (1988 to Sanofi Aventis France).
- ^ Serge Petit, et al. EP0273199 (1988 to Sanofi Aventis France).
- .
- ^ Xavier Emonds-Alt, Patrick Gueule, Vincenzo Proietto, Didier Van Broeck, U.S. patent 5,679,693 (1997 to Sanofi SA).
- ^ Xavier Emonds-Alt, et al. U.S. patent 5,554,763 (1996 to Sanofi SA).
- PMID 22757.
- PMID 18561912.
- ^ Sharma H, Santra S, Dutta A. Triple reuptake inhibitors as potential next-generation antidepressants: a new hope? Future Med Chem. 2015;7(17):2385-406. doi: 10.4155/fmc.15.134. Epub 2015 Nov 30. PMID 26619226; PMCID: PMC4976848.
- ^ Chen Z, Skolnick P. Triple uptake inhibitors: therapeutic potential in depression and beyond. Expert Opin Investig Drugs. 2007 Sep;16(9):1365-77. doi: 10.1517/13543784.16.9.1365. PMID 17714023.
- ^ Skolnick P, Basile AS. Triple reuptake inhibitors ("broad spectrum" antidepressants). CNS Neurol Disord Drug Targets. 2007 Apr;6(2):141-9. doi: 10.2174/187152707780363285. PMID 17430151.
- PMID 21174473.
- PMID 20527970.
- ^ Bettati M, Cavanni P, Di Fabio R, Oliosi B, Perini O, Scheid G, Tedesco G, Zonzini L, Micheli F. Oxa-azaspiro derivatives: a novel class of triple re-uptake inhibitors. ChemMedChem. 2010 Mar 1;5(3):361-6. doi: 10.1002/cmdc.200900482. PMID 20112329.
- S2CID 45400599.
- PMID 2999402.
- ^ Jan Kehler, Friedrich Kroll, & Karsten Juhl, WO2006007843 (to H Lundbeck AS).
- PMID 18499098.
- ^ PMID 10737754.
- ^ WO 2005041875, Kozikowski, Alan P. & Zhou, Jia, "Dopamine-, norepinephrine- and serotonin- transporter- selective heterocyclic compounds and their therapeutic applications", published 2005-05-12, assigned to Georgetown University
- ^ PMID 20864506.
- PMID 12951108.
- ^ Christopher David Beadle, et al. WO2005000811 (to Eli Lilly and Co).
- ^ Clark, B. P.; Cases-Thomas, M. J.; Gallagher, P. T.; Gilmore, J.; Masters, J. J.; Timms, G. H.; Whatton, M. A.; Wood, M.Preparation of N,N-disubstituted 4-aminopiperidines as inhibitors of monoamine, in particular serotonin, norepinephrine, and dopamine reuptake. WO2004052858 (2004 to Eli Lilly and Co Ltd (GB)).
- ^ Boulet, S. L.; Clark, B. P.; Fairhurst, J.; Gallagher, P. T.; Johansson, A. M.; Whatton, M. A.; Wood, M. Preparation of 4-aminopiperidine derivatives as monoamine uptake inhibitors. WO2005092885 (2005 to Eli Lilly And Company).
- S2CID 5654856.
- ^ Criado, Elisa (2 May 2014). "A fast-acting antidepressant could be on the horizon". The Independent. Retrieved 22 June 2014.
- ^ "A novel triple reuptake inhibitor with rapid antidepressant properties identified by virtual screening (1144.1)". Archived from the original on 2015-09-24. Retrieved 2014-06-23.
- ^ "A new fast-acting antidepressant (That's not ketamine) shows promise". Los Angeles Times. May 2014.
- ^ "Fast-acting antidepressant appears within reach".
- PMID 23892272.
- ^ Mondeshka, Diana; Angelova, Ivanka; Ivanov, Chavdar B.; Ivanova, Nedjalka S. (1990). "Racemische und optisch aktive 2-Chlorethylcarbamoyl-Derivate des 7,8-Dimethoxy-1-phenyl-1H-3-benzazepins: Neue Strukturtypen von DA, NE und 5-HT Uptake Inhibitoren". Archiv der Pharmazie. 323 (10): 829–832. doi:10.1002/ardp.19903231003.
- ^ PMID 12723940.
- S2CID 6812669.
- ^ Hache, G.; Guiard, B.P.; Nguyen, T.H.; Quesseveur, G.; Gardier, A.M.; Peters, D.; Munro, G.; Coudoré, F. (2015). "Antinociceptive activity of the new triple reuptake inhibitor NS18283 in a mouse model of chemotherapy-induced neuropathic pain". European Journal of Pain. 19 (3): 322–333. doi:10.1002/ejp.550.
- ^ Birgitte L. Eriksen, et al. WO2008025777 (2008 to Neurosearch A/S).
- ^ Dan Peters, et al. U.S. patent 7,060,699 (2006 to NeuroSearch AS).
- ^ Peter Moldt, Jørgen SCHEEL-KRÜGER, Gunnar M. Olsen, Elsebet Østergaard NIELSEN , WO1997013770 (1997 to Neurosearch A/S).
- ^ Liming Shao, 12 More », WO2008151156 (to Sunovion Pharmaceuticals Inc.).
- ^ Shao, Liming; Hewitt, Michael C.; Wang, Fengjiang; Malcolm, Scott C.; Ma, Jianguo; Campbell, John E.; Campbell, Una C.; Engel, Sharon R.; Spicer, Nancy A.; Hardy, Larry W.; Schreiber, Rudy; Spear, Kerry L.; Varney, Mark A. (2011). "Discovery of N-methyl-1-(1-phenylcyclohexyl) methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters. 21 (5): 1438–1441. doi:10.1016/j.bmcl.2011.01.016.
- ^ Shao, Liming; Hewitt, Michael C.; Wang, Fengjiang; Malcolm, Scott C.; Ma, Jianguo; Campbell, John E.; Campbell, Una C.; Engel, Sharon R.; Spicer, Nancy A.; Hardy, Larry W.; Schreiber, Rudy; Spear, Kerry L.; Varney, Mark A. (2011). "Discovery of N-methyl-1-(1-phenylcyclohexyl) ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters. 21 (5): 1434–1437. doi:10.1016/j.bmcl.2011.01.019.
- ^ Shao L, Li W, Xie Q, Yin H. Triple reuptake inhibitors: a patent review (2006 - 2012). Expert Opin Ther Pat. 2014 Feb;24(2):131-54. doi: 10.1517/13543776.2014.859676. Epub 2013 Nov 30. PMID 24289044.
- ^ Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA. Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21. PMID 21093273.
- ^ Liming Shao, et al. WO2007081542 (Sunovion Pharmaceuticals Inc).
- ^ Liming Shao & Jianguo Ma, WO2010091268 (Sunovion Pharmaceuticals Inc).
- ^ Heike Radeke & Liming Shao, US7812035 (2003 to Sunovion Pharmaceuticals Inc).
- ^ Liming Shao, et al. US8592608, US9133117 & US9850204 (2018 to Sunovion Pharmaceuticals Inc).
- ^ Ishichi, Yuji; Kimura, Eiji; Honda, Eiji; Yoshikawa, Masato; Nakahata, Takashi; Terao, Yasuko; Suzuki, Atsuko; Kawai, Takayuki; Arakawa, Yuuichi; Ohta, Hiroyuki; Kanzaki, Naoyuki; Nakagawa, Hideyuki; Terauchi, Jun (2013). "Novel triple reuptake inhibitors with low risk of CAD associated liabilities: Design, synthesis and biological activities of 4-[(1S)-1-(3,4-dichlorophenyl)-2-methoxyethyl]piperidine and related compounds". Bioorganic & Medicinal Chemistry. 21 (15): 4600–4613. doi:10.1016/j.bmc.2013.05.025.
- ^ Ishichi Yuji, Kimura Eiji & Terauchi Jun, WO2010016554 (to Takeda).
- ^ Kaur H, Izenwasser S, Verma A, Wade D, Housman A, Stevens ED, Mobley DL, Trudell ML. Synthesis and monoamine transporter affinity of 3alpha-arylmethoxy-3beta-arylnortropanes. Bioorg Med Chem Lett. 2009 Dec 15;19(24):6865-8. doi: 10.1016/j.bmcl.2009.10.087. Epub 2009 Oct 23. PMID 19896846; PMCID: PMC2788963.
- PMID 7623609.
- ^ U.S. patent 4,556,676
- ^ Li N, Li C, Han R, Wang Y, Yang M, Wang H, Tian J. LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain. Front Pharmacol. 2019 Feb 14;10:53. doi: 10.3389/fphar.2019.00053. PMID 30837867; PMCID: PMC6382704.
- ^ Zhang, Fangxi; Shao, Jing; Tian, Jingwei; Zhong, Yan; Ye, Liang; Meng, Xiangjing; Liu, Qiaofeng; Wang, Hongbo (2016). "Antidepressant-like Effects of LPM580153, A Novel Potent Triple Reuptake Inhibitor". Scientific Reports. 6 (1). doi:10.1038/srep24233.
- S2CID 37122044.
- ^ Hou, Jian; Xing, Yanli; Zuo, Daiying; Wu, Yingliang; Tian, Jingwei; Meng, Qingguo; Yang, Mina (2015). "In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor". Physiology & Behavior. 138: 141–149. doi:10.1016/j.physbeh.2014.10.007.
- ^ S2CID 12635418.
- ^ Shaw AM, Boules M, Zhang Y, Williams K, Robinson J, Carlier PR, Richelson E. Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050. Eur J Pharmacol. 2007 Jan 19;555(1):30-6. doi: 10.1016/j.ejphar.2006.10.004. Epub 2006 Oct 17. PMID 17109850.
- ^ Liu, Shuang; Zha, Congxiang; Nacro, Kassoum; Hu, Min; Cui, Wenge; Yang, Yuh-Lin; Bhatt, Ulhas; Sambandam, Aruna; Isherwood, Matthew; Yet, Larry; Herr, Michael T.; Ebeltoft, Sarah; Hassler, Carla; Fleming, Linda; Pechulis, Anthony D.; Payen-Fornicola, Anne; Holman, Nicholas; Milanowski, Dennis; Cotterill, Ian; Mozhaev, Vadim; Khmelnitsky, Yuri; Guzzo, Peter R.; Sargent, Bruce J.; Molino, Bruce F.; Olson, Richard; King, Dalton; Lelas, Snjezana; Li, Yu-Wen; Johnson, Kim; Molski, Thaddeus; Orie, Anitra; Ng, Alicia; Haskell, Roy; Clarke, Wendy; Bertekap, Robert; O’Connell, Jonathan; Lodge, Nicholas; Sinz, Michael; Adams, Stephen; Zaczek, Robert; Macor, John E. (2014). "Design and Synthesis of 4-Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors". ACS Medicinal Chemistry Letters. 5 (7): 760–765. doi:10.1021/ml500053b.
- ^ Shuang Liu, Bruce F. Molino, Kassoum Nacro, WO2010132442 (2010 to Albany Molecular Reserch, Inc.). Page column 32.
- ^ Ki-Ho Lee, et al. WO2009148291 (to SK Biopharmaceuticals Co Ltd).
- ^ Chun-Eung Park, et al. WO2009148290 (to SK Biopharmaceuticals Co Ltd).
- ^ Lee KH, Park CE, Min KH, Shin YJ, Chung CM, Kim HH, Yoon HJ, Won-Kim, Ryu EJ, Shin YJ, Nam HS, Cho JW, Lee HY. Synthesis and pharmacological evaluation of 3-aryl-3-azolylpropan-1-amines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors. Bioorg Med Chem Lett. 2010 Sep 15;20(18):5567-71. doi: 10.1016/j.bmcl.2010.07.021. Epub 2010 Aug 17. PMID 20724153.
- ^ Koprdova R, Csatlosova K, Durisova B, Bogi E, Majekova M, Dremencov E, Mach M. Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors. Molecules. 2019 Nov 20;24(23):4218. doi: 10.3390/molecules24234218. PMID 31757051; PMCID: PMC6930491.
- ^ Weng, Zhijie; Zheng, Yongyong; Li, Jianqi (2015). "Synthesis, Antidepressant Activity, and Toxicity of the Erythro/Threo Racemates and Optical Isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-ol". Chemical Biology & Drug Design. 85 (4): 454–460. doi:10.1111/cbdd.12438.
- ^ Honda, Eiji; Ishichi, Yuji; Kimura, Eiji; Yoshikawa, Masato; Kanzaki, Naoyuki; Nakagawa, Hideyuki; Terao, Yasuko; Suzuki, Atsuko; Kawai, Takayuki; Arakawa, Yuuichi; Ohta, Hiroyuki; Terauchi, Jun (2014). "Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors". Bioorganic & Medicinal Chemistry Letters. 24 (16): 3898–3902. doi:10.1016/j.bmcl.2014.06.046.
- ^ Paudel, Suresh; Acharya, Srijan; Yoon, Goo; Kim, Kyeong-Man; Cheon, Seung Hoon (2017). "Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors". Bioorganic & Medicinal Chemistry. 25 (7): 2266-2276. doi:10.1016/j.bmc.2017.02.051
- ^ Paudel, Suresh; Min, Xiao; Acharya, Srijan; Khadka, Daulat Bikram; Yoon, Goo; Kim, Kyeong-Man; Cheon, Seung Hoon (2017). "Triple reuptake inhibitors: Design, synthesis and structure–activity relationship of benzylpiperidine–tetrazoles". Bioorganic & Medicinal Chemistry. 25 (20): 5278–5289. doi:10.1016/j.bmc.2017.07.046
- ^ Paudel S, Wang S, Kim E, Kundu D, Min X, Shin CY, Kim KM. Design, Synthesis, and Functional Evaluation of 1, 5-Disubstituted Tetrazoles as Monoamine Neurotransmitter Reuptake Inhibitors. Biomol Ther (Seoul). 2021 Nov 18. doi: 10.4062/biomolther.2021.119. Epub ahead of print. PMID 34789584.
- ^ Han, Minsoo; Song, Chiman; Jeong, Nakcheol; Hahn, Hoh-Gyu (2014). "Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine". ACS Medicinal Chemistry Letters. 5 (9): 999–1004. doi:10.1021/ml500187a.
- ^ Yun, Jun; Han, Minsoo; Song, Chiman; Cheon, Seung Hoon; Choi, Kihang; Hahn, Hoh-Gyu (2014). "Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors". Bioorganic & Medicinal Chemistry Letters. 24 (15): 3234–3237. doi:10.1016/j.bmcl.2014.06.026.
- ^ Mondeshka DM, Angelova IG, Tancheva CN, Ivanov CB, Daleva LD, Ivanova NS. Synthesis, antiulcer and antidepressive activity of 4-(4-halophenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolines. Farmaco. 1994 Jul-Aug;49(7-8):475-80. PMID 7945712.
- ^ CA2015114 idem Donka M. Mondeshka, 10 More », EP0400319 (1990 to N I S Pri Vchti).
- ^ James P. Beck, Mark A. Smith, Matt A. Curry, M. A. Aryl- and heteroarylsubstituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin. WO2001032625 (2001 to Du Pont Pharmaceuticals Company).
- ^ Zheng YY, Guo L, Zhen XC, Li JQ. Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as triple reuptake inhibitors. Eur J Med Chem. 2012 Aug;54:123-36. doi: 10.1016/j.ejmech.2012.04.030. Epub 2012 Apr 30. PMID 22608762.
- ^ Han Y, Han M, Shin D, Song C, Hahn HG. Exploration of novel 3-substituted azetidine derivatives as triple reuptake inhibitors. J Med Chem. 2012 Sep 27;55(18):8188-92. doi: 10.1021/jm3008294. Epub 2012 Sep 11. PMID 22938049.
- ^ Roggen, Heidi; Kehler, Jan; Stensbøl, Tine Bryan; Hansen, Tore (2007). "Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters". Bioorganic & Medicinal Chemistry Letters. 17 (10): 2834–2837. doi:10.1016/j.bmcl.2007.02.054.
- PMID 19427589.
- S2CID 1518033.
- Universite de Rouen
- PMID 21205415.
- S2CID 31553844.
- S2CID 207331897.
- PMID 1976813.
- PMID 21258088.
- PMID 9599245.
- ^ PMID 15957006.
- ^ U.S. patent 6,395,748
- ^ U.S. patent 6,376,673
- ^ WO 2004039778, Wätjen, Frank, "Novel piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-05-13, assigned to NeuroSearch AS
- ^ U.S. patent 7,560,562
- ^ Archived at Ghostarchive and the Wayback Machine: "2010 N.C. Award for Science: Dr. F. Ivy Carroll". YouTube.
- PMID 15566309.
- ^ Abuse, National Institute on Drug. "Drug-Related Hospital Emergency Room Visits". www.drugabuse.gov. Retrieved 2016-04-04.
- ^ PMID 17258302.
- ^ S2CID 39794215.
- ^ PMID 11990077.
- PMID 17825265.
- PMID 19710631.
- PMID 21228061.
- PMID 19086767.
- PMID 19766133.
- S2CID 9205978.
- S2CID 205929292.
- PMID 16213110.
- PMID 15283948.
- S2CID 70385136.
- PMID 11408518.
- S2CID 39849071.
- PMID 22169943.
- ^ PMID 19442174.
- ISBN 9780071481274.
Pharmacologic observations such as these led to a simple hypothesis: depression is the result of inadequate monoamine neurotransmission, and clinically effective antidepressants work by increasing the availability of monoamines. Yet this hypothesis has failed to explain the observation that weeks of treatment with antidepressants are required before clinical efficacy becomes apparent, despite the fact that the inhibitory actions of these agents—whether in relation to reuptake or monoamine oxidase—are immediate. This delay in therapeutic effect eventually led investigators to theorize that long-term adaptations in brain function, rather than increases in synaptic norepinephrine and serotonin per se, most likely underlie the therapeutic effects of antidepressant drugs. Consequently, the focus of research on antidepressants has shifted from the study of their immediate effects to the investigation of effects that develop more slowly. The anatomic focus of research on antidepressants also has shifted. Although monoamine synapses are believed to be the immediate targets of antidepressant drugs, more attention is given to the target neurons of monoamines, where chronic alterations in monoaminergic inputs caused by antidepressant drugs presumably lead to long-lasting adaptations that underlie effective treatment of depression. The identification of molecular and cellular adaptations that occur in response to antidepressants, and the location of the cells and circuits in which they occur, are the chief goals that guide current research. The work described toward the beginning of the chapter on mood-regulating circuits that involve the subgenual cingulate gyrus, for instance, represent a significant advance over a narrow focus on monoamine neuron function. ...
The several weeks latency in onset of the therapeutic actions of antidepressants contributes to distress and clinical risk for those with severe depression. In the search for treatments of more rapid onset, great effort has gone into trying to understand the delay in efficacy of current antidepressants. All current ideas posit that antidepressant-induced increases in synaptic monoamine concentrations cause slowly accumulating adaptive changes in target neurons. Two broad classes of theories have emerged: (1) Changes in protein phosphorylation, gene expression, and protein translation occur in target neurons that ultimately alter synaptic structure or function in a way that relieves symptoms; and (2) antidepressant-induced neurogenesis in the hippocampus and the incorporation of those new neurons into functional circuits is a required step in the therapeutic response. Before considering specific hypotheses, however, it is important to discuss obstacles in relating research in animal models to human depression. - S2CID 42407412.
- S2CID 221395033.
- ^ S2CID 29459098.
- PMID 5319766.
- ^ "Joseph J. Schildkraut | Harvard Medical School Office for Faculty Affairs". Archived from the original on 2011-07-19. Retrieved 2011-03-09.
- PMID 16121130.
- ^ http://www.healyprozac.com/Book/Introduction.pdf [bare URL PDF]
- ^ PMID 17017959.
- PMID 8629887.
- PMID 15688090.
- PMID 131359.
- S2CID 34523310.
- S2CID 2139339.
- S2CID 18005398.
- S2CID 6886384.
- S2CID 45520438.
- PMID 17403963.
- S2CID 35761979.
- PMID 18425966.
- S2CID 206054231.
- PMID 21155988.
- PMID 18476671.
- S2CID 10488057.
- S2CID 38643068.
- S2CID 45621773.
- S2CID 19966517.
- PMID 21107146.
- ^ PMID 25813654.
- S2CID 239077479.
External links
- Media related to Serotonin–norepinephrine–dopamine reuptake inhibitors at Wikimedia Commons