17 replies to this topic

[Flex]

Hi there,

 

I´ve recently learned that Magnolia officialis compounds have  CB1 agonist/antagonist, cb2 partial agonist and Gpr55 antagonist properties.

As You know, posses the CB2 receptor some antipsychotic properties and the antipsychotic action of canabidiol (CBD) are related to its GPR55 blocking properties which is sometimes called CB3 receptor.

 

Brain cannabinoid CB2 receptor in schizophrenia.

http://www.ncbi.nlm....pubmed/19931854

 

Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB2 Receptors and Blockade of the Related GPR55

The bark of Magnolia officinalis is used in Asian traditional medicine for the treatment of anxiety, sleeping disorders, and allergic diseases. We found that the extract and its main bioactive constituents, magnolol and honokiol, can activate cannabinoid (CB) receptors. In cAMP accumulation studies, magnolol behaved as a partial agonist (EC50 = 3.28 μM) with selectivity for the CB2 subtype, while honokiol was less potent showing full agonistic activity at CB1 and antagonistic properties at CB2. We subsequently synthesized the major metabolites of magnolol and found that tetrahydromagnolol (7) was 19-fold more potent than magnolol (EC50 CB2 = 0.170 μM) exhibiting high selectivity versus CB1. Additionally, 7 behaved as an antagonist at GPR55, a CB-related orphan receptor (K B = 13.3 μM, β-arrestin translocation assay). Magnolol and its metabolites may contribute to the biological activities of Magnolia extract via the observed mechanisms of action. Furthermore, the biphenylic compound magnolol provides a simple novel lead structure for the development of agonists for CB receptors and antagonists for the related GPR55.

http://www.ncbi.nlm....pubmed/24900561

 

 

Furthermore I´ve found that Quercetin has inverse agonism properties at the Cb1 receptor.

 

Homology modelling of CB1 receptor and selection of potential inhibitor against Obesity

http://www.ncbi.nlm....les/PMC3398776/

 

But I rather avoid it since it increases my "special" depression and it impairs Synaptic transmission

 

Quercetin targets cysteine string protein (CSPalpha) and impairs synaptic transmission.

http://www.ncbi.nlm....pubmed/20548785

 

Echinacea purpurea has some CB2 activating properties

Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts.

http://www.ncbi.nlm....pubmed/19303464

 

 

 

I would be glad if someone knows any additional CB1 antagonists or Gpr55 antagonists

and could show a source of tetrahydromagnolol. (maybe a groupbuy ?)

So I welcome any related discussion about CB ligands and the alteration or modification (e.g. Epigenetic) of cannabinoid signaling.

Edited by Flex, 24 July 2014 - 04:06 PM.

[Flex]

Voacanga inhibits potently the CB1 receptor

 

Discovery of indole alkaloids with cannabinoid CB1 receptor antagonistic activity.

http://www.ncbi.nlm....pubmed/21376588

Three indole alkaloids, voacamine (1), 3,6-oxidovoacangine (2), and a new alkaloid, 5-hydroxy-3,6-oxidovoacangine (3), isolated from Voacanga africana were found to exhibit potent cannabinoid CB1 receptor antagonistic activity. This is the first example of CB1 antagonists derived from natural alkaloids

 

And its a TRP antagonist which afaik could counter some effects of Cannabis but i must read further to confirm this.

Activation and inhibition of thermosensitive TRP channels by voacangine, an alkaloid present in Voacanga africana, an African tree.

http://www.ncbi.nlm....pubmed/24484240

 

Something off topic but interresting regarding Voacanga:

Analysis of African plant reveals possible treatment for aging brain

http://www.salk.edu/...p?press_id=2040

 

Voacanga is afaik related with Iboga.

I just wanted to mention, that at least Iboga can be fatal even at therapeutic doses due to something like

cardiovascular disturbances !?

I´ve forgotten the exactly cause, but wanted only to mention that it maybe could also happen with Voacanga.. dont know.

So please investigate propperly, before usage.

Edited by Flex, 04 August 2014 - 06:43 PM.

[medievil]

Sounds like weak stuff, CB1 antagonists are antipsychotic, CB2 agonists are proposed for shizophrenia, a combination of rimonabant with a synthetic cannabinoid would provide this.

[Flex]

Are You referring to Magnolia or Voacanga ?

Edited by Flex, 08 August 2014 - 08:08 PM.

[Flex]

Further Antagonists would be Falcarinol and Tetrahydrocannabivarin.

 

I wonder where to buy Falcarinol ..

[maxwatt]

Cannabidiol...

 

[Flex]

Thanks but CBD is allready well known for blocking GPR55 and is relative easy obtainable.

 

Its hard to find a relative potent CB1 or CB2 antagonist.

 

CDB is a weak antagonist according to this abstract:

Are cannabidiol and Δ9 -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review.

Based on evidence that the therapeutic properties of Cannabis preparations are not solely dependent on the presence of Δ9 -tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9 -tetrahydrocannabivarin (THCV).

Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid type-1 (CB1 ) receptors, thus behaving like first generation CB1 inverse agonists, such as rimonabant. Here we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent preclinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action, and thus appear very unlikely to produce unwanted central nervous system effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low affinity CB1 ligand which can nevertheless affect CB1 activity in vivo in an indirect manner,

whilst THCV is a high affinity CB1 ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 antagonism. THCV also has high affinity for CB2 and signals as a partial agonist, a departure from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology, and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.

 

Moreover CBD enhances the endocanabinoids via degradation inhibition:

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

http://www.nature.co.../tp201215a.html

 

But I´ve read also the opposite..

 

 

Edited by Flex, 18 November 2014 - 04:48 PM.

[Flex]

Found this:

The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonists.

http://www.ncbi.nlm....pubmed/19359525

 

Tea catechins' affinity for human cannabinoid receptors.

Competitive radioligand binding assays using recombinant human cannabinoid receptors expressed in Chem-1 and CHO cells identified (-)-epigallocatechin-3-O-gallate, EGCG (K(i)=33.6 microM), (-)-epigallocatechin, EGC (K(i)=35.7 microM), and (-)-epicatechin-3-O-gallate, ECG (K(i)=47.3 microM) as ligands with moderate affinity for type 1 cannabinoid receptors, CB1. Binding to CB2 was weaker with inhibition constants exceeding 50 microM for EGC and ECG

http://www.ncbi.nlm....pubmed/19897346

 

[mwestbro]

Your first citation was retracted: http://jpet.aspetjou...t/330/1/31.long

Here is the text of the retraction: http://jpet.aspetjou...1/1.1/suppl/DC1

Edited by mwestbro, 18 March 2015 - 02:50 PM.

[gamesguru]

Curcumin & resveratrol....(Ki values of 5.9 and 45 nM, respectively) 

 

THC has a Ki of 5.05 nM, so it's good the study was retracted, as experience tells us curcumin + black pepper is non-intoxicating.

 

 

EGCG (K(i)=33.6 microM

you'd need 5-50 grams to feel intoxicated.

and this is old news; it should be to every long time member

[Flex]

Just wanted to repeat it, because I havent found it on longecity.

[Flex]

Found this:

Identification of CB1/CB2 ligands from Zanthoxylum bungeanum.

http://www.ncbi.nlm....pubmed/24175626

 

The objective of this screen was to identify novel antagonists of the CB1 receptor, which simultaneously displayed agonist activity against the CB2 receptor, since compounds matching this criterion could be potential candidates for the treatment of type-1 diabetes. As a result, two Z. bungeanum extracts were deemed active, leading to the identification of eight compounds, of which compound 7 [(2E,4E,8E,10E,12E)-N-isobutyl-2,4,8,10,12-tetradecapentaenamide, γ-sanshool] was obtained as a promising lead compound.

 

Altough I´m not able to find any informations about the affinity.

Edited by Flex, 18 March 2015 - 09:50 PM.

[Arjuna]

Neat thread.  If there were some alternative to Marijuana that give similar effects in terms of creativity it would be so freaking awesome.  I can kinda get there with Theanine and it's promotion of alpha waves, but it's not the same.

 

Edit: I've also tried echinacea, may have eased basal anxiety but isn't the creative lubricant that MJ is. 

Edited by Arjuna, 20 March 2015 - 05:20 PM.

[Flex]

Kava Kava has some relative weak CB1 activating properties as well as Maca and Magnolia,

but Kava and Magnolia have some very sedating actions, I would choose Kava among them two because its a mao-b inhibitor.

I cant say much about the potency of Maca, it was annoying enough for me ^^ altough I havent smoked pot for a long time when tried it, so it could be weak for You.

[Flex]

Passionflower has seemingly some antagonistic effects on the CB1 receptor. I can say anything about the affinity:

Effects of Passifl ora incarnata L. on rat hippocampal G protein-coupled receptor

http://www.passionsb...2010_Poster.pdf

 

As well as Kanna/Zembrin/Sceletium tortuosum but seemingly rather weak

Zembrin (Kanna)

http://www.longecity...na/#entry722001

 

[Flex]

mTor1 inhibition depress overactivation of CB1 receptors as well as dopamine D3 and 5-ht6 in the PFC:

Brain targets

http://www.longecity...-brain-targets/

 

or directly the table 2 :

www.nature.com/nrd/journal/v11/n2/fig_tab/nrd3628_T2.html

 

From:

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

www.nature.com/nrd/journal/v11/n2/full/nrd3628.html

 

 

 

 

Edited by Flex, 14 April 2015 - 05:46 PM.

[Flex]

A metabolite of Magnolia compunds is an antagonist of GPR55

 

Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB2 Receptors and Blockade of the Related GPR55

http://pubs.acs.org/....1021/ml300235q

 

(CBD)

 

Cannabidiol is a negative allosteric modulator of the type 1 cannabinoid receptor

http://onlinelibrary....13250/abstract

[Flex]

X link to my other THC thread

http://www.longecity...se/#entry729209