Monday, October 12, 2020

Obscure and Unknown: Heterocyclic amine/Competitive antagonist Dissociatives

*WARNING* The substances mentioned in this series have little to no record of human use, and thus the effects they have on humans are either poorly understood or entirely unknown. Much of what this information is simply hypotheses based on animal trials or very small human sample sizes. Very little information exists about their acute or long-term toxicity. Under no circumstances should any of these substances be ingested by a human outside of a clinical setting where psychological and physiological effects can be closely monitored and extremely precise doses can be prepared and TITRATED. DO NOT seek any of these out if you do not have access to those resources.

Hello I have been caught in a firestorm of different activities but I didn't forget about this series! I certainly have not updated in a while. But I have something new for everyone- Today we will be looking at a series of dissociatives based on the structure of a heterocyclic amine. Heterocyclic amines are unique in how they cause dissociative effects- quite different from all of the familiar NMDA antagonists!

Heterocylclic amine? What does that mean? Let's break it down! A cyclic molecule is a bunch of carbons bonded to each other in a ring. Hetero-means different, so that means something other than a carbon is sitting in that ring. Amine is an amine, nitrogen, etc. so a heterocyclic amine is a ring shaped molecule with a nitrogen in there somewhere! In this case these are saturated heterocyclic rings, which means we just see single bonds between the carbons.

Both compounds listed here are what are called "Allosteric modulators" of the NMDA receptor. What does this mean? Well, first lets talk about what an NMDA receptor does- you can envision the NMDA receptor as a sort of gate made of several different components, a gate that separates the inside of a nerve cell (aka the neuron) from the synapse, a small space that insulates it from an adjacent nerve cell. By default, the gate is closed. However, this gate has keys, that must be used in tandem to unlock it. When the neurotransmitters glutamate or NMDA bind to this gate at the same time as the amino acid glycine, the receptor changes its configuration and opens up, allowing ions to flow from the synapse into the cell, allowing an electric impulse to be passed from neuron to neuron. When something interferes with this process, you have a breakdown of communication between cells, giving us the familiar "dissociative" effects of NMDA antagonists. Most familiar NMDA antagonists like PCP and ketamine work by simply wedging themselves into the channel that was opened by Glutamate/NMDA,  and physically blocking ions from passing through. Allosteric modulators however, bind elsewhere to the molecule, triggering a reaction that affects its shape and function. Glutamate/NMDA and glycine are allosteric modulators of the receptor in that they triggers it to change to an open position. Other allosteric modulators however will interfere with that reaction and keep it closed. A competitive antagonist will rush in and block the spot that either Glutamate/NMDA or glycine are supposed to bind to before they can get there, meaning the receptor will never open in the first place. Noncompetitive antagonists will bond to a different part of the receptor, simply not allowing it to open. With our gate analogy, channel blockers are like sticking a boulder in the opening of the gate after it's been opened, competitive antagonists are like filling one of the keyholes with superglue so that the keys can't be used, and noncompetitive antagonists are like gluing the hinges still, so that even when all the components are there the gate still won't open. Both compounds we will look at today are different kinds of competitive antagonist.

The specific compounds we will be looking at here are two pharmaceutical candidates that were, per usual, abandoned due to their "undesirable side effects". These compounds are called Selfotel and HA-966.

Let's just dive right in.


The structure of HA-966

HA-966 is an NMDA antagonist that consists of a pyrrolidine ring with a number of substitutions- 1-HO, 2-Oxo, and 3-amino. It is structurally similar to the neurotransmitter GABA, the main depressive neurotransmitter, though GABA occurs as a straight chain, while HA-966 comes in the form of a ring.

HA-966 was first developed in the 1960s and published in 1971, where its structural similarity to GABA was noted. Thus, the effects it had on animals, such as catalepsy and sedation, were attributed to that mode of action and it was for a time regarded as a run of the mill depressant [1]. It was later determined to be an NMDA antagonist, the specific mechanism of which being fully characterized in vitro in 1989, as a glycine binding antagonist, different from the familiar NMDA antagonists [2]. I explain what this means in the next paragraph. Another study went on to demonstrate that the different enantiomers had different effects, where the (+) enantiomer was an NMDA antagonist while the (-) enantiomer was something more of a sedative similar to GBL [3]. Thus a racemic mixture of the drug would present an interesting combination of sedative and dissociative activity.

Foster and Kemp demonstrated in [2] that HA-966 was a different sort of NMDA antagonist than we're used to. As mentioned before, drugs like PCP and ketamine are channel blockers, that physically wedge into the channel of the NMDA receptor, blocking it [4]. HA-966 is a bit different however- it is an allosteric inhibitor. In the intro, there was an analogy that the NMDA receptor is like a gate, opened with 2 keys, NMDA and glycine. HA-966 is a glycine antagonist, meaning it wedges itself into the keyhole glycine is supposed to enter, preventing the fate from opening. We have almost no examples of what sort of experience this kind of NMDA antagonist yields in humans for reference. A study with rats however showed that when trained to discriminate between different drugs, they treated HA-966 different from PCP, indicating some sort of qualitative difference [5]. It's been in fact demonstrated that HA-966 will actively inhibit the action of PCP or MK-801 when administered concurrently [6].

So all of this dense data goes on to say: HA-966 is an NMDA antagonist, and will likely act as a dissociative, but with a mechanism of action unlike any dissociative that's been ingested by humans, save for the noble gas Xenon. So what happens when you give it to a person? Well the reason I know about it in the first place is that intrepid reddit users recently blazed this trail. 

I source these descriptions from a series reddit posts. The first is from u/Strangetimer, who shared a live report of their experience [7].

A dose of 100 mg + 50 mg + 100 mg sublingually proved to be as such:

(At 100 mg) "Certainly feeling dissociated but not in a dreamlike/euphoric way like with opiates or alcohol. It almost feels like I'm a bit anesthetized. Extreme reduction in pain sensation, unsteady gait, feeling somewhat mentally/physically dampened, and my peripheral vision has become incredibly dark and blurry. I can only read something when I'm looking directly at it. So far it is incredibly unique."

(At 150 mg)  "Second dose is now kicked in. Feeling heavily sedated. If I close my eyes for too long I could easily fall asleep. This now feels remarkably similar to alcohol physically, however mentally there is much less disinhibition/euphoria. My mind almost feels "cleared" similar to antipsychotics and it's hard for me to focus on one thing for too long."

(At 250 mg) "Physical impairment is now severe, mental impairment however is relatively low. Can still think fairly clearly, however acting on anything is difficult...Right there is a notable difference from alcohol/benzos. Unlike benzos I’m very aware that I’m pretty messed up and unlike alcohol I don’t have the “fuck it” attitude that makes long treks through the snow and cold more bearable."

A second report from u/StoopSign with a presumably oral dose of 120 mg stated [8]:

"thought I'd close my eyes for mild dissociation and of course I holed TF out completely and totally. I only know the amount of time it lasted because of songs on a list playing throughout. I may have been fully unconscious for a few mins. It wasn't until I realized I couldn't move and fully anaesthesiiazed off some unknown shit and about to OD from some bad drug combo"

(It should be stated that this user had also consumed a number of GABAergic sedatives throughout the day prior to this experience)

This information seems to indicate that HA-966 is a uniquely sedating and physically incapacitating dissociative with a fairly lucid headspace. It appears to be a relatively short duration experience, in the range of about 3-5 hours. It shows great promise and it would be interesting to explore further, especially from those well versed in typical ion-blocker type dissociatives who could draw comparisons between the different mechanisms of action!

There were a few cursory explorations into its potential in human as a neuroprotective, sedative, and anticonvulsant, though these were never explored much further in humans. It has found new legs in the nootropics market. 

Structure of Selfotel

Selfotel (aka CGS-19755) is another heterocyclic amine, like HA-966, though there are a number of superficial differences between the two. For one- Selfotel is a 6 member ring, while HA-966 is a 5 member ring! HA-966 is a tertiary amine (there are things other than hydrogen bonded to all 3 spots of the nitrogen), while Selfotel is a secondary amine (there is one hydrogen bonded to the nitrogen). Selfotel also has various substitutions around its ring, namely a 2-Carboxyl group and a 4-phosphonate. However, HA-966 has the distinction of being a direct variant of the neurotransmitter GABA, while Selfotel is just kinda its own thing.

Like HA-966, Selfotel is a competitive NMDA antagonist, meaning it also clogs one of the keyholes on the receptor, preventing it from opening. While HA-966 blocks the Gylcine keyhole, Selfotel blocks the other one, the hole for the neurotransmitter NMDA that the receptor is named for [9]. This would also suggest that it has unique qualitative properties relative to the familiar ion channel antagonists.

Selfotel was, similar to Aptiganel, developed for treatment of situations that caused an excessive and toxic release of glutamate, like stroke or head injury. Also like Aptiganel, certain "side effects" led to the eventual abandonment of development.

It was first studied in 1988, where it was identified as an NMDA antagonist [10]. Further investigation into its potential as an anticonvulsant/anxiolytic/anti-ischemic raised it into the world of pharmacological development [11]. An animal study elaborated on its analgesic and motor effects, an indicator of a potentially interesting NMDA antagonist [12]. One other study corroborated an observation with HA-966: that competitive antagonists produce an experience in animals that is unique from the typical channel blockers, and that they can be reliably expected to produce a unique subjective experience in humans [13]. 

All of this goes to say- scientists found this drug very interesting and sought further development. Unfortunately, it would follow a very similar trajectory to that of Aptiganel. Similar to Aptiganel, Selfotel ran up against the absurd issue that it was actually potentially deadlier than administering nothing at all [14]. A drug that may be toxic in stroke victims is certainly the opposite of a treatment for stroke. This is explored in further detail in the aptly named analysis "Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two Phase III clinical trials" by Morris M.D. et al, 1999 [15]. 

Other very interesting effects also detracted from its candidacy as a pharmaceutical. Most notably, what one study referred to as "PCP-like behavioral effects" in animals [16]. I cannot find the full version of this paper for free unfortunately so I am not sure on the details of that, but the abstract states that such effects presented only from exceptionally high doses of Selfotel, well beyond the therapeutic range. Unfortunately, as stated before, I can't access this paper so I am not sure what dose that is. A therapeutic dose is indicated ~2 mg/kg or 140 mg in a 150 lb (70 kg) person. No subjective descriptions of the effects in humans seem to exist. Similar to Aptiganel, it is determinedly probably not safe to take Selfotel if you have recently had a stroke or head injury, as it seems to be specifically counterindicated in those cases (even though that is what it was developed for! oops.)

Development of Selfotel never really went any further. Perhaps researchers were leary with the concurrent failures of Aptiganel. Unlike Aptiganel, Selfotel never went on to tank its development company. Much less of a problem child. 

It also probably bears mentioning Midafotel, (aka CPPene or SDZ EAA 494) which bears a similar structure and activity to Selfotel, though it utilizes a Piperazine ring instead of a Piperidine (that means there's 2 nitrogens).
Structure of Midafotel

Midafotel has a similar pharmacological action to Selfotel and perhaps suggests some ways in which the structure of Selfotel can be modified to retain activity- The phosphonate occurs as a trans-phosponate across a butene chain which is an interesting modification- it is also bonded to a nitrogen, forming a tertiary amine that's absent in selfotel. Midafotel was developed for similar reasons as Selfotel, and has a similar highly selective competitive NMDA antagonist activity. Its development was ultimately abandoned as it showed no efficacy for its intended purpose, though there were no reports of dissociative effects. The closest were some patients citing memory problems during trials. [18]


So there we have it, these are 2 examples of heterocyclic amines that act as dissociatives. It is interesting that they share a different mechanism of action than the usual channel blockers. Seeing as they are active, this opens the door perhaps to other competitive antagonists as interesting and active compounds. Whether all single heterocyclic amine ring based dissociatives are competitive antagonists is unknown- various mixing and matching of the substitutions has not yet been attempted- HA-966 seems to be a unique GABA-adjacent structure and probably can't risk much modification. As for selfotel- it seems the phosphonate group carries some essential function in binding to the NMDA receptor, as can be seen in other similar non-analgesic NMDA antagonists like Perzinfotel [17]. However, the Carboxylic acid bonded to the amine mimics a portion of the neurotransmitter NMDA, so perhaps that is indispensable too. So maybe there isn't much wiggle room to modify these unique compounds, though someone else may know better than me,

Sources and Further Reading:
[1]- Bonta IL, De Vos CJ, Grijsen H, Hillen FC, Noach EL, Sim AW (1971) 1-Hydroxy-3-amino-pyrrolidone-2(HA-966): a new GABA-like compound, with potential use in extrapyramidal diseases. Br J Pharmacol. 43(3):514-35
[2]- Foster A, Kemp J (1989). HA-966 antagonizes N-methyl-D-aspartate receptors through a selective interaction with the glycine modulatory site. The Journal of neuroscience : the official journal of the Society for Neuroscience 
[3]- Singh L, Donald AE, Foster AC, Hutson PH, Iversen LL, Iversen SD, Kemp JA, Leeson PD, Marshall GR, Oles RJ, Priestly T, Thorn L, Tricklebank MD, Vass CA, Williams BJ (1990) Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative. Proc Natl Acad Sci U S A. 87(1):347-51
[4]- Waterhouse RN (2003) Imaging the PCP site of the NMDA ion channel. Nucl Med Biol. 30(8):869-78.
[5]- Singh L, Menzies R, Tricklebank MD (1990) The discriminative stimulus properties of (+)-HA-966, an antagonist of the glycine/N-methyl-D-aspartate receptor. European Journal of Pharmacology 186(1):129-132
[6]- Bristow LJ, Hutson PH, Thorn L, Tricklebank MD (1996) The glycine/NMDA receptor antagonist, R-(+)-HA-966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK-801) in rodents. Br J Pharmacol.108(4):1156-63
[9]- Baron SP, Woods JH (1995) Competitive and uncompetitive N-methyl-D-aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine. Psychopharmacology 118:42–51
[10]- Lehmann J, Hutchison AJ, McPherson SE, Mondadori C, Schmutz M, Sinton CM, Tsai C, Murphy DE, Steel DJ, Williams M, et al. (1988) CGS 19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino acid receptor antagonist. J Pharmacol Exp Ther. 246(1):65-75
[11]- Bennett DA, Lehmann J, Bernard PS, Liebman JM, Williams M, Wood PL, Boast CA, Hutchison AJ (1990) CGS 19755: a novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist with anticonvulsant, anxiolytic and anti-ischemic properties. Prog Clin Biol Res. 361:519-24
[12]- France CP, Winger GD, Woods JH (1990) Analgesic, anesthetic, and respiratory effects of the competitiveN-methyl-d-aspartate (NMDA) antagonist CGS 19755 in rhesus monkeys. Brain Research 526(2):355-358
[13]- Baron SP, Woods JH (1995) Competitive and uncompetitive N-methyl-D-aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine. Psychopharmacology 118: 42-51
[14]- Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, Norris J (2000) Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist. Stroke 31(2):347-54
[15]- Morris GF, Bullock R, Marshall SB, Marmarou A, Maas A, Marshall LF (1999) Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators. J Neurosurg 91(5):737-43
[16]- Bennett DA, Bernard PS, Amrick CL, Wilson DE, Liebman JM, Hutchinson AJ (1989) Behavioral pharmacological profile of CGS 19755, a competitive antagonist at N-methyl-D-aspartate receptors. Journal of Pharmacology and Experimental Therapeutics 250(2):454-460
[17]- Kinney WA, Abou-Gharbia M, Garrison DT, Schmid J, Kowal DM, Bramlett DR, Miller TL, Tasse RP, Zaleska MM, Moyer JA (1998) Design and Synthesis of [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)- ethyl]phosphonic Acid (EAA-090), a Potent N-Methyl-d-aspartate Antagonist, via the Use of 3-Cyclobutene-1,2-dione as an Achiral α-Amino Acid Bioisostere. J. Med. Chem. 41(2):236-246
[18]- Rockstroh S, Emre M, Pokorny R, Tarral A (1996) Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans. Psychopharmacology 124:261-266

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