NMD blockers and depression

[Jamshyd]

I'll start with this:

Enhancement of antidepressant-like effects but not BDNF mRNA expression by the novel NMDA receptor antagonist neramexane in mice.

Kos T, Legutko B, Danysz W, Samoriski G, Popik P.

Laboratory of Behavioral Neuroscience, Institute of Pharmacology, Polish Academy of Sciences, Krakow.

Improved efficacy in the treatment of depression may be achieved by the combined use of several antidepressants. In the present study, acute administration of the novel NMDA receptor antagonist, neramexane, as well as the representative antidepressants imipramine, fluoxetine and venlafaxine, shortened the duration of immobility in the mouse tail suspension test with a minimal effective dose (MED) of 5 mg/kg. When tested in combination, the antidepressant-like effects of 5 mg/kg of imipramine, 20 mg/kg of fluoxetine and 5 mg/kg of venlafaxine were potentiated by neramexane (2.5 mg/kg), a dose which alone did not produce a significant effect on the duration of immobility. These effects appeared to be specific because they were not accompanied by significant effects on locomotor activity. The enhanced antidepressant-like activity produced with the different combinations was not synergistic as determined by comparing the theoretical and observed ED50s for each combination. In separate experiments, Northern blot analysis showed that a 14-day treatment with imipramine (10 mg/kg, b.i.d) increased brain-derived neurotrophic factor (BDNF) mRNA expression in the cortex while neramexane (5 mg/kg, b.i.d.) decreased it. Combined treatment produced no effect on BDNF mRNA expression. Mice treated with imipramine or neramexane for 14 days and tested shortly after the last dose demonstrated significant shortening of immobility, and the combined treatment produced an even greater antidepressant-like effect. Together these data support the view that NMDA receptor antagonists enhance the potency of antidepressants, but leave open the question as to whether enhanced BDNF expression is a necessary feature of the antidepressant-like effect.

You may discuss this as much or as little as you want, I just found it interesting.

What I want to discuss is your feelings about NMDA blockers (mainly glutamate site antagonists) and their anti-depressant like effect. Do a search if interested in acadamic lit. (or I can do one later, I keep most of the ones I find saved on my HD).

From personal experience, as some of you may know, I have found daily sub-psychedelic (and of course, sub- sub-anaesthetic) doses of Ketamine (about 10-25mg intranasally) to be effective against bipolar depression (severe; think suicidal). I did not find any of the other available NMDA blockers as effective, but they were better than nothing in some respects. Here is a quick rundown of my own experiences with items that have NMDA-blocking qualities one way or another (all used in daily sub-rectreational doses for a week at least):

PCP: Somewhat effective, but with some err.. loopy side effects . I could not go beyond 4 days with this stuff since as you'd expect effects are cumulative, so by day 3 I was actually high most of the day...

DXM: Not very effective. In fact it seems to make my depression worse! Also, yucky physical side-effects, like irritable bowels and upset stomach.

Cat's claw and L-Theanine (not used together): These are both weak NMDA antagonists, and they both seem to have a very slight effect (Theanine the better of the two) but cannot be considered effective. Interesting to note: at higher doses they feel very DXM-like at lower plateau doses...

Supplementation with Magnesium and/or Zinc: I sometimes get fits of Anorexia with my depressive episodes, and therefore bad nutrition. I found that suppelemeting with these two (I tried mixed and separate supplements), especially when combined, was very good in battling depression and especially the accompanying anxiety.

[As an aside, I found Nitrous Oxide to be fantastic for instant relief of depression, but rather short-lived in effect (no longer than 5 hours). I do not know if it has been confirmed that the main action of N2O is NMDA-related though.]

- I would really love to experiment with Adamantine-type drugs (such as Memantine) which have notable DA agonism; and with Opoids with notable NMDA-antagonist effects (such as Methadone), as "maintinance" type antidepressants (my depression seems completely biochemical and no ammount of therapy or spiritual work seems to help. It comes in strikes and goes just as suddenly as it comes - for no reason at all - leaving me in a nutty, "easy-on-the-powder" kind of personality) . The reason is because Ketamine, in addition to its main effect as an NMDA-antagonist, has also notable DA and Opioid activity (thanks for all the useful info, F&B!). I have suspicions that this triad of effects is the key to battling [my?] strong melancholia.

What I also would like to note from personal experience, is that things that are primarily Opioid (such as morphine) and things that are primarily dopaminergic (such as amphetamine) were VERY useful for interrupting depression, but NOT useful AT ALL for "maintinance" (the latter being more useless than the former... I take low (80 - 100mgish) daily doses of Codeine since it is OTC here, and it seems to help a little, but for all I know it could be placebo.) Neither were usefull long-term not only for the obvious dependence issues, and not only because they lose efficacy over time, but also as many of you here know but tend to forget: that interrupting them leaves one in a prolonged state of artificial depression worse than the one that started the whole thing!

... Then again, it does seem like Opiates themselves have blocking effects on NMDA receptors, just to make things more confusing, hehe.

Thanks for reading my long charlatan rant. Feel free to comment on any part of it.

 

[sylvan Wanderer]

I am diagnosed ADHD and for the next day or so after I take a ritalin ( i do so infrequently) I am very calm and peaceful (i have diagnosed ocd and undiagnosed social anxiety). SOmetimes the day after moderate drinking i get the same feeling. Both work on dopamine to some extent and I read social anxiety has to do with dopamine. But, as you say dopamine alone doesn't seem to be the culprit.

I am interested in the zinc/magnesium supplementation (dose/time frame) as this seems like a simple and effective solution.

 

[Jamshyd]

Thanks for reminding me - I forgot to mention Alcohol (another substance with NMDA-antagonist effects). Alcohol - at any dose - doesn't seem to do much for my depression but it worsens my "breaks" of (hypo)mania between one episode of depression and the other, even with a single drink (and I have a very high natural tolerance to it, even though I don't drink). Sp for example, as you can guess from my verbose posts after a long absence, I am currently craving a drink for no reason, and I know I would become an egoistic psycho if I had this drink now.

Ketamine and other NMDA antagonists seem to just neutralize the two. Now that I haden't had access to Ketamine for a three or four months, my temperament both ways tends to be extreme, and without my 2g/day of gabapentin (with occasional amphet. and benzo supplement) I'd likely be a lunatic (of course I adamantly refuse to take SSRI-like junk, Valproic shit and Antpsychotic garbage - btw, I have sampled all but the major anticonvulsants and Lithium, which I still refuse to get near me!).

Like you say, dopaminergics seem good for short-term use. I also get the same effect from ritalin and coca tea (I feel that cocaine is just overdosing on coca - it is an utter failture even as a local anaesthetic since coca works just fine!). But they simply stop working after a week or so.

Sorry if this includes a lot of agenda... just thought I'd add my 2c

As for Zn/Mg... remember that these are needed for proper NMDA antagonism. I found they worked best when my diet was certainly lacking many essential nutrients (ie. when I stop eating for several days, usually during my mania, which of course leads to a crash). For doses, I take 500mgish of Magnesium and 30mg of Zinc, both amino-acid bound (or equivalent) each night. I will not hide though, that even with a healthy diet, supplementation with these two always parallelled a more balanced mood and thought. Could be placebo.

 

[Jamshyd]

Btw, if you look up neramexane (mentioned in above abstract), it looks a lot like memantine that was blown wide open with explosives. haha.

 

[streetsurfer]

What I also would like to note from personal experience, is that things that are primarily Opioid (such as morphine) and things that are primarily dopaminergic (such as amphetamine) were VERY useful for interrupting depression, but NOT useful AT ALL for "maintinance" (the latter being more useless than the former... I take low (80 - 100mgish) daily doses of Codeine since it is OTC here, and it seems to help a little, but for all I know it could be placebo.) Neither were usefull long-term not only for the obvious dependence issues, and not only because they lose efficacy over time, but also as many of you here know but tend to forget: that interrupting them leaves one in a prolonged state of artificial depression worse than the one that started the whole thing!

Man, it is like you have known me my whole life, lol, I feel exactly the same. NOTHING works like a small dose of Ketamine to make me feel grounded, free, and myself but of course it fuckin tolerence

As for what you mentioned above, I have often wondered about a cycling regime to overcome tolerence issues. It is done with antibiotics for people with chronic infects, why not nmda antagonists?

As per that study you posted, why not take several weak nmda antagonists and see if you can combinethe synergistically to get a good effect?

Magnesium as NMDA receptor blocker in the traditional Chinese medicine Danshen.

Sun X, Chan LN, Sucher NJ.

Department of Biology, Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China.

Aqueous extracts of the traditional Chinese medicine Danshen, the dried roots of Salvia miltiorrhiza Bunge (Labiatae), blocked N-methyl-D-aspartate (NMDA) evoked currents in cerebrocortical neurons in vitro. The block of the NMDA-evoked currents was voltage dependent and showed the negative slope conductance reminiscent of the effect of Mg2+ ions. Atomic absorption spectrophotometry (AAS) revealed that aqueous Danshen extracts contained approximately 9mM magnesium. Fractionation of the extracts by high performance liquid chromatography followed by patch clamp recording and AAS indicated that magnesium ions were present in two distinct fractions. One fraction contained approximately 5 mM magnesium and blocked NMDA-induced currents indicating that it contained mostly free Mg2+ ions, while a second fraction did not possess NMDA antagonist activity despite the presence of approximately 4 mM magnesium suggesting that Mg2+ in this fraction was mostly chelated. Following removal of the free Mg2+ by ion exchange chromatography, the previously observed block of the NMDA-induced currents was abolished. These data demonstrate that Danshen contains both free and chelated Mg2+. Free Mg2+ ions account for the NMDA antagonist activity of Danshen in vitro.

Can someone clarify the above for me? Are the saying that it is just magnesium same as u would get in your diet causes this or that it delivers magnesium to the nmda recptor complex and that is how it has its action?

This is a fucking amazing drug, read the following

Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine.

Wang R, Yan H, Tang XC.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China.

Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase(AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.

 

[Jamshyd]

Thanks for the post streetsurfer

If I had time I'd post and comment more lit. Maybe later today..

But I wanted to mention Huperzine A:

I had experience with his material, although I have only ever taken it in combination with vinpocetin - so I dont know which did what, but I have to say that this is the only "nootropic" that ever did anything to me. It has a very positive effect on mood and I'd rate it even higher than PCP in terms of efficacy.

 

[streetsurfer]

bump

 

[streetsurfer]

I had experience with his material, although I have only ever taken it in combination with vinpocetin - so I dont know which did what, but I have to say that this is the only "nootropic" that ever did anything to me. It has a very positive effect on mood and I'd rate it even higher than PCP in terms of efficacy.

Thats quite a statement. Is it something u can use as an antidepressant and still funtion, will you build a tolerence?

 

[crOOk]

Thats quite a statement. Is it something u can use as an antidepressant and still funtion, will you build a tolerence?

Hmmm, I think I have something to add here...

DMX and PCP have an amazing afterglow attached to them that make me manic for days. Ketamine lacks that quality. I have holed on ketamine around hundred times and used PCP 3-4 months straight every day with a four day break in month 3.

In fact ketamine doesn't only lack this mania inducing quality for me, but does the opposite. It will make me feel extremely bad for at least one day after use. I will have very low self esteem and feel really insecure and anxious, similar to what pot use sometimes (!) does.

Everytime I have (tried to) quit drugs it happened after heavy dissociative use. In the case of Phencyclidine (first time use, one experience only) it just happened because I felt soooooo good forthe next days. I didn't even relate it to the exprience of the other day back then, but searched for all kinds of reasons why I felt soooo good. It was insane, I was seriously manic. The effects are the strongest after about 15-25 hours when the inhibition of coordinative skills subsided and they slowly fade within the next 1-2 weeks.

In the case of Ketamine I usually quit because I felt really bad. I reached the bottom. It was like someone held as mirror in front of me and said: Look what you have done. That's how your drug use makes you feel. It usually happens after disappointing, unexciting k experiences (there aren't any "bad" k experiences for me, even if I end up waking up in a pile of puke next to a trashcan full of piss.).

DXM behaves similar to PCP for me, I've only had <20 experiences with it. In the higher dosis range (500+ mg) it will have this SUPEReuphoric afterglow to it as well.

It's actually the most intense and most naturally feeling euphoria I have come to know. The only way to top it is to consume psychedelics during the afterglow.

Anyway, it helped me so much that I actually started to smoke pcp daily. I considered both DXM and PCP use for the purpose of treating my "depression" if you can call it that. I had a once per week use in mind. The first and maybe second day I might feel insanely good, but after that it would mostly prevent my crashing.

I didn't think about the addictive properties of the dissociative experience itself though... :/ Didn't really work out after all. Ended up using it daily starting at day one of my antidepressant dissociative use experiment.

But still, I think if you would supply certain NMDA antagonists to people who are not as prone to substance dependence as I am, they could have some serious potential!!!

crOOk

 

[Dr.Heckyll]

There's a recent study lending credibility to your ketamine antidepressant story:

Arch Gen Psychiatry. 2006 Aug;63(8):856-64. Links
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK.
Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, MD 20892, USA. [email protected]

CONTEXT: Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health.Patients Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

PMID: 16894061

 

[Dr.Heckyll]

There's a recent study lending credibility to your ketamine antidepressant story:

Arch Gen Psychiatry. 2006 Aug;63:856-64.
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK.
Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, MD 20892, USA. [email protected]

CONTEXT: Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health.Patients Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

PMID: 16894061

 

[crOOk]

This is an oooold threat... But there's been a lot of developement. So I thought I'd update you guys with a few links, hoping to spark a little discussion and speculation. Since after all, a large part of this community seems to be a victim of self medicating the imbalances in their brain chemistry with psychotropic drugs... Hope you enjoy this!

Ok, I'm not an expert on the subject... In fact, I don't know jack besides what bluelight and wikipedia teaches me... But the way I understand it is that the non-selective NMDA antagonists raise the relative activity of AMPA receptors (through endogenous mechanisms).
So they've basically been looking into which NMDA receptor subtype is responsible for the antidepressant effects of non-selective NMDA antagonists and are trying to target this one without the "psychotomimetic" (lol!) / dissociative "side effects" (lol again!) of Ketamine and the like. Additionally it is debated if there can be selective AMPA agonists that stabilize these antidepressant effects. Quite hot if you ask me!
Now it seems they've actually developed a compound that targets specifically the NRB2 subtype of the NMDA receptors! And by now, they even have a trivial name for it: Traxoprodil! Oh glory.
Here's a link, I can't find half the other links I was gonna post, but googling for "NRB2 antagonist", NMDA antidepressant, AMPA antidepressant etc. yielded some very good results

compound description: http://www.curehunter.com/public/keywordSummaryC095106-traxoprodil-mesylate.do
CAS-number, structure: http://www.axonmedchem.com/product/1406cp101606.html
major study differentiating it's effects from those of non-selective NMDA antagonists http://egret.psychol.cam.ac.uk/hannah/Guscott_2003_EJPharm_CP101606_watermaze.pdf

EDIT: Clinicaltrials.gov also reports about a study conducted by Pfizer in 2006 which aimed at finding out the effectiveness of Traxoprodil as a treatment for Major Depressive Disorder in a clinical trial. THe internal identifier number on clinicaltrials.gov is NCT00163059. Unfortuantely, I wasn't able to find any sort of results. If anyone is more lucky than me, please update thwe thread or write me a pm.

EDIT2: Never mind, I found some bits on pubmed, might be another study: http://www.ncbi.nlm.nih.gov/pubmed/19011431?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

 

[Hammilton]

Traxoprodil is a sweet lookin structure.

I thought it looked familiar; it reminds me a lot of fentanyl and bromidol.

 

[crOOk]

...

BACKGROUND: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. METHODS: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. RESULTS: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. CONCLUSIONS: NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
Source: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17643398&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

 

[hugo24]

..RESULTS: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. ..

Looks like we have to bear those bad side effects of Ketamine

Otoh it looks like CP101606 produces also dissociative effects :

http://www3.interscience.wiley.com/journal/121392001/abstract

"Abstract

Glutamate antagonists decrease dyskinesia and augment the antiparkinsonian effects of levodopa in animal models of Parkinson's disease (PD). In a randomized, double-blind, placebo-controlled clinical trial, we investigated the acute effects of placebo and two doses of a NR2B subunit selective NMDA glutamate antagonist, CP-101,606, on the response to 2-hour levodopa infusions in 12 PD subjects with motor fluctuations and dyskinesia. Both doses of CP-101,606 reduced the maximum severity of levodopa-induced dyskinesia 30% but neither dose improved Parkinsonism. CP-101,606 was associated with a dose-related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects "

 

[seep]

Btw, if you look up neramexane (mentioned in above abstract), it looks a lot like memantine that was blown wide open with explosives. haha.

I wish someone with good SAR insight would comment further on this. The molecule is flexible, whereas amantidine and memantine are locked into an adamantane cage and therefore rigid. But in what seems to be the most stable conformation of neramexane, the methyls that have been "blasted open" have coplanar carbons.

 

[crOOk]

Bad news for the depressed folk waiting for glutamate receptor based antidepressants...

The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys
Authors: Katherine L Nicholson, Robert S Mansbach, Frank S Menniti, Robert L Balster
Development of N-methyl-D-aspartate (NMDA) antagonists for a variety of disorders has been hindered by their production of phencyclidine (PCP)-like psychological effects and abuse potential. There is, however, evidence to suggest that this problem might be mitigated by targeting NMDA receptors subtypes, in particular, those containing the NR2B subunit. To further test this hypothesis, the NR2B selective antagonist CP-101 606 (traxoprodil) was evaluated in two animal models: drug discrimination, a model of the subjective effects of drugs in humans, and self-administration, which evaluates the reinforcing properties of the drug. In the first study, CP-101 606(3-300 microg/kg/infusion) was tested for intravenous self-administration in rhesus monkeys experienced in PCP (5.6 microg/kg/infusion, intravenously) self-administration. In the second study, CP-101 606 was tested for production of PCP-like discriminative stimulus effects in rats (3-56 mg/kg, intraperitoneally) and rhesus monkeys (0.3-5.6 mg/kg intravenously). Evidence was obtained for reinforcing effects of at least one dose of CP-101 606 in all four monkeys. In rats, CP-101 606 produced more than 80% mean PCP-lever selection (2.0 mg/kg, intraperitoneally) but, unlike PCP itself, the dose producing the highest level of substitution was accompanied by more than 50% suppression of response rates. In monkeys, CP-101 606 produced more than 90% PCP-lever selection (0.1 mg/kg intramuscularly) in three of four animals at doses that did not significantly decrease rates of responding. The data show that CP-101 606 has some PCP-like discriminative stimulus effects in rats and monkeys and functions as a positive reinforcer in monkeys. These results suggest that inhibition of NR2B subunit containing NMDA receptors plays a role in the production of the subjective effects and abuse potential associated with many subtype-nonselective NMDA receptor antagonists such as PCP.