N-3′-ethylaplysinopsin and related alkaloids

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N-3′-ethylaplysinopsin and related alkaloids

Postby sage-borodin » Sun May 14, 2017 9:35 am

Smenospongia aurea is a fascinating marine organism which produces a fascinating array of indole alkaloids, all with many potentials.

6-bromo-2'-de-N-methylaplysinopsin and N-3′-ethylaplysinopsin particularly piqued my interest.

A new indole alkaloid, N-3′-ethylaplysinopsin (68), isolated from the Jamaican sponge Smenospongia aurea, was shown to potently bind to the human serotonin 5-HT2C receptor subtype expressed in a mammalian cell line (Hu et al., 2002). The authors suggest that the R2 functional groups at position 2′ may play an important role in regulating subtype selective binding to the 5-HT2C receptor, a receptor found in high density in the choroid plexus, the site of cerebrospinal fluid production.

The high affinity for agonism at 5HT2a and 5HT2c receptor subtypes displayed by some of these compounds particularly caught my attention.

Other research outlining Smenospongia aurea and the compounds which it produces:
New antiinfective and human 5-HT2 receptor binding natural and semisynthetic compounds from the Jamaican sponge Smenospongia aurea.
In addition to the sesquiterpene-phenol aureols (1), 6'-chloroaureol (2), and aureol acetate (3), eight indole alkaloids including the new N-3'-ethylaplysinopsin (9) have been isolated from the Jamaican sponge Smenospongia aurea. Makaluvamine O (10), a new member of the pyrroloiminoquinone class, was also isolated. The structures were characterized by spectroscopic methods, and two new derivatives of aureol were prepared to optimize the biological activity. Aureol N,N-dimethyl thiocarbamate (1a) and 6-bromoaplysinopsin (7) exhibit significant antimalarial and antimycobacterial activity in vitro. Compound 6 showed activity against the Plasmodium enzyme plasmepsin II. The 6-bromo-2'-de-N-methylaplysinopsin (6), 6-bromoaplysinopsin (7), and N-3'-ethylaplysinopsin (9) displaced high-affinity [(3)H]antagonist ligands from cloned human serotonin 5-HT(2) receptor subtypes, whereas the other compounds tested did not. Remarkably, the 6-bromo-2'-de-N-methylaplysinopsin (6) showed a > 40-fold selectivity for the 5-HT(2C) subtype over the 5-HT(2A) subtype.

Here some of the potential functions of these compounds are outlined:
Marine monoindole alkaloids, sharing structure similarities with serotonin, are certain to become useful tools to facilitate the understanding of serotonin receptor function and generate new drug leads for the treatment of depression, anxiety, migraines and other 5HT receptor related disorders

The structural similarity of indole alkaloids to endogenous amines and neurotransmitters has led researchers to postulate the possible neurological activity of these molecules. Several compounds carrying an indole moiety have been reported to possess affinity towards different serotonin receptors: barettin, 8,9-dihydrobarettin,13 tris-indole alkaloids gelliusine A and B,14 and σ-conotoxin.15 Methylaplysinopsin (1) (Fig. 2) isolated from Aplysinopsis reticulata by Baird-Lambert et al. was reported to inhibit monoamine oxidase (MAO) and to displace serotonin from its receptors.16 Other molecules from this group: 6-bromo-2′-de-N-methylaplysinopsin (2), 6-bromoaplysinopsin (3), and N-3′-ethylaplysinopsin (4) (Fig. 2) isolated from Smenospongia aurea were reported to displace high-affinity antagonist binding for human 5-HT2C and 5-HT2A receptors.17 N-3′-ethylaplysinopsin did not display selectivity to either of these two receptors (Ki of 3.5 μM and 1.7 μM for 5HT2C and 5HT2A receptor, respectively). 6-Bromoaplysinopsin showed only low selectivity towards 5HT2C receptors (Ki 0.33 μM and 2.0 μM for 5HT2C and 5HT2A receptor, respectively); however 6-bromo-2′-de-N-methylaplysinopsin exhibited strong (40 fold) selectivity to 5HT2C receptors (Ki 2.3 μM for 5HT2C and >100 μM for 5HT2A). Besides neurological activity, 6-bromoaplysinopsin also showed significant activity against Plasmodium falciparum.

5,6-dibromo-N,N-dimethyltryptamine (5)18 and 5-bromo-N,N-dimethyltryptamine (6)19 (Fig. 3) exhibited antimicrobial activity as reported by Tymiak.20 The dibrominated compound was significantly more active over the monobromotryptamine. Both of the compounds were also found to possess neurological activity: 5,6-dibromo-N,N-dimethyltryptamine showed antidepressant action in forced swim test and tail suspension test;21,22 5-bromo-N,N-dimethyltryptamine exhibited strong sedative effect in the locomotor activity test.


Smenospongia aurea is a fascinating organism, it is also the natural source of a known psychedelic brominated tryptamine compound, namely 5-bromo-N,N-Dimethyltryptamine.

Here, in TIHKAL, shulgin comments on these brominated marine tryptamines:
The compound with a methoxy group substituent at the 1-position is called Lespedamine, 1-MeO-DMT. With an NO bond, this should be classified as a substituted hydroxylamine. I would love to know if anyone anywhere has ever tried smoking it. I suspect it might very well be active, but it is, to my knowledge, untried. I wonder why it deserves a trivial name, vis., Lespedamine? Two additional ring-substituted derivatives of DMT come from the marine world. 5-Bromo-DMT and 5,6-dibromo-DMT are found in the sponges Smenospongia auria and S. echina resp. I have no idea if they are active by smoking (the 5-Br-DMT just might be) but they are quantitatively reduced to DMT by stirring under hydrogen in methanol, in the presence of palladium on charcoal. A very closely related sponge, Polyfibrospongia maynardii, contains the very closely related 5,6-dibromotryptamine and the corresponding monomethyl NMT. I had the fantasy of trying to scotch the rumor I'm about to start, that all the hippies of the San Francisco Bay Area were heading to the Caribbean with packets of Zig-Zag papers, to hit the sponge trade with a psychedelic fervor. This is not true. I refuse to take credit for this myth.

First, on an unrelated note 1-MeO-DMT was given the name Lespedamine is named as such due to its occurrence in the Lespedeza bicolor plant.
Second, in relation to the following TIHKAL excerpt: 5-Bromo-DMT and 5,6-dibromo-DMT are found in the sponges Smenospongia auria and S. echina resp. I have no idea if they are active by smoking (the 5-Br-DMT just might be). The activity of 5-bromo-DMT has been anecdotally confirmed, a pseudonymous chemist calling himself "doctor osculum" sent a message to vice media reporter Hamilton Morris describing the synthesis and qualitative effects produced by 5-Br-DMT, this is outlined in the following link. https://www.vice.com/en_us/article/sea-dmt-000481-v20n3

I apologize for the "thrown together" and hectic format of this post, it's a complex area of research with many facets and intricacies, and in my enthusiasm for the matter I often "jump around" or provide disorganized information while trying to include every detail in a single post. I am also aware that I left out quite a bit, but it is a starting point, which should be further refined and organized over time.
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Re: N-3′-ethylaplysinopsin and related alkaloids

Postby sage-borodin » Thu May 25, 2017 8:47 am

The affinity constants to serotonin receptor subtypes 5-HT2A and 5-HT2C are presented in Table 2. Compounds 4, 5 and 11 showed high affinity to the 5-HT2C receptor. In addition, aplysinopsins 5 and 11 showed also affinity to the 5-HT2A subtype. The highest affinity to 5-HT2C was established for 6-bromoaplysinopsin (5), with a Ki value similar to that of serotonin. Compounds 4 and 11 had only 4 to 20% of the activity of serotonin
https://www.ncbi.nlm.nih.gov/pmc/articl ... s-07-00166

See attached image; compounds are numbered as listed below in the attached research, an excerpt of which is cited above, the entire research paper can be viewed in the supplied link.
·Compound #2 = isoplysin a
·Compound #2 = 2'-de-N-methyl-aplysinopsin
·Compound #6 = 6-bromo-2'-de-N-methyl-applysinopsin
·Compound #5 = 6-bromo-aplysinopsin
·Compound #7 = Methylaplysinopsin
·Compound #11 = N-3′-ethylaplysinopsin ]

These 2-aminoimidazoline substituted indole marine alkaloids are fascinating, specially in regard to their 5HT2a/5HT2c receptor agonism. These receptors play a crucial role in the pharmacology of psychedelic substances, as demonstrated below:
Investigations conducted over the past 3 decades have demonstrated that serotonergic receptors, specifically the 5-HT2A and 5-HT2C subtypes, play an important role in the behavioral effects of hallucinogenic compounds. The present study was designed to determine the respective significance of these two receptors in the stimulus effects of LSD and (-)DOM in the rat. Specifically, the interactions of a series of serotonergic antagonists (risperidone, pirenpirone, metergoline, ketanserin, loxapine, LY53857, pizotyline, spiperone, cyprohepatadine, mesulergine, promethazine, and thioridazine) with the LSD stimulus and the (-)DOM stimulus in LSD-trained subjects was defined. From these data, IC50 values were determined for the inhibition of the LSD-appropriate responding elicited by either 0.1 mg/kg LSD (15-min pretreatment time) or 0.4 mg/kg (-)DOM (75-min pretreatment). In addition, the affinities of these antagonists for 5-HT2A and 5-HT2C receptors were determined in radioligand competition studies, 5-HT2A affinity correlated significantly with IC50 values for the blockade of the LSD (r = +0.75, P < 0.05) and (-)DOM (r = +0.95, P < 0.001) stimuli in the LSD trained subjects. 5-HT2C affinity did not correlate significantly with either series of IC50 values. These data indicate that (1) the stimulus effects of LSD, and (2) the substitution of (-)DOM for the LSD stimulus are mediated by agonist activity at 5-HT2A receptors.

So what is the psychedelic significance of these novel marine aplysinopsins? Specially in regard to the 5HT2a/c agonist pharmacology demonstrated by several of these compounds?
t2-marinedrugs-07-00166.png (16.46 KiB) Viewed 75 times
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Re: N-3′-ethylaplysinopsin and related alkaloids

Postby sage-borodin » Tue May 30, 2017 8:52 am

As I'm sure most of you are aware, the one pharmacological commonality shared by these psychedelic substances Is agonism at the 5HT2a/c receptor sites, and while these compounds may have action at other receptor sites, their primary activity seems to be heavily linked to these serotonin receptor subtypes.

When one is given a 5HT2a/c antagonist, the psychedelic effect of these compounds will be greatly diminished, if not entirely extinguished. This is further demonstrated through research using "5HT2a/c knockout mice", these mice were genetically altered to not produce 5HT2a/c receptors.
(This has led me to speculate that genetics relating 5HT2a/c receptors that one produces has an effect on the manner in which an individually individual will react to these compounds, but that's another topic.)

5HT2a/c receptor agonism is necessary, but does not seem to be sufficient to generate psychedelic effect.
Evidence from studies with phenylisopropylamine hallucinogens indicates that the 5HT2A receptor is the likely target for the initiation of events leading to hallucinogenic activity associated with LSD and related drugs. Recently, lisuride (a purported non-hallucinogenic congener of LSD) was reported to be a potent antagonist at the 5HT2C receptor and an agonist at the 5HT2A receptor. LSD exhibited agonist activity at both receptors. These data were interpreted as indicating that the 5HT2C receptor might be the initiating site of action for hallucinogens. To test this hypothesis, recombinant cells expressing 5HT2A and 5HT2C receptors were used to determine the actions of LSD and lisuride. LSD and lisuride were potent partial agonists at 5HT2A receptors with EC50 values of 7.2 nM and 17 nM, respectively. Also, LSD and lisuride were partial agonists at 5HT2C receptors with EC50 values of 27 nM and 94 nM, respectively. We conclude that lisuride and LSD have similar actions at 5HT2A and 5HT2C receptors in recombinant cells. As agonist activity at brain 5HT2A receptors has been associated with hallucinogenic acitivity, these results indicate that lisuride may possess hallucinogenic activity, although the psychopharmacological effects of lisuride appear to be different from the hallucinogenic effects of LSD.
https://link.springer.com/article/10.10 ... 85?LI=true

Further research:

Gonzalez-Maeso J, Weisstaub N, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon S.

“Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior”.
Neuron. 2007 Feb 1;53(3):439-452.

Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT2A receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric Gi/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Behavioral effect/2,5-dimethoxy-4-iodo-amphetamine research.
Although it is well established that hallucinogens act as 5-HT2A and 5-HT2C receptor agonists, little is known about the relative contributions of 5-HT2A and 5-HT2C receptors to the acute behavioral effects of these drugs. The behavioral pattern monitor was used to characterize the effects of the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on locomotor and investigatory behavior in mice. Studies were also conducted to assess the contributions of 5-HT2A and 5-HT2C receptors to the behavioral effects of DOI. DOI produced an inverted U-shaped dose response function, with lower doses (0.625–5.0 mg/kg) increasing and higher doses (≥10 mg/kg) decreasing locomotor activity. The increase in locomotor activity induced by 1.0 mg/kg DOI was absent in 5-HT2A receptor KO mice, suggesting the involvement of 5-HT2A receptors. The reduction in locomotor activity produced by 10 mg/kg DOI was potentiated in 5-HT2A KO mice and attenuated by pretreatment with the selective 5-HT2C/2B antagonist SER-082. These data indicate that the decrease in locomotor activity induced by 10 mg/kg DOI is mediated by 5-HT2C receptors, an interpretation that is supported by the finding that the selective 5-HT2C agonist WAY 161,503 produces reductions in locomotor activity that are potentiated in 5HT2A KO mice. These results demonstrate for the first time that 5-HT2A and 5-HT2C receptors both contribute to the effects of DOI on locomotor activity in mice. Furthermore, these data also suggest that 5-HT2A and 5-HT2C receptors exert opposing effects on locomotor activity.

So while agonism of these receptor subtypes is necessary, but not sufficient, I feel these 2-aminoimidazoline substituted indole marine alkaloids are a worthwhile research venture.

Actually, Smenospongia aurea and the novel indole compounds which it produces may ultimately prove to be of great value to many people working in many different fields, let's not forget that 5-bromo-dimethyltryotamine and 5,6-dibromo-dimethyltryptamine have both been researched for many valuable applications, 5-bromo-DMT appears to have anti-depressant activity when consumed orally, and psychedelic effect when smoked
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