Cannabinoids and chemical classes

[highonmt]

Some interesting posts here regarding 'cannabinoid free' [chemotype v] cannabis got me thinking about cannabinoids as a class and the distinctions between cannabinoids as compounds that show affinity for cb1 and cb2 and the benzo chromene type compounds produced by cannabis that are the 'classic' cannabinoids. Many people use the term cannabinoid to refer specifically to these benzo cromene

and acyclic benzo terpenens

type compounds produced in cannabis.

In reality there are a number of compounds found in cannabis that are indeed cannabinoids due simply to their affinity for the cb1 and 2 receptors. Terpenes such as beta caryophyllene [cb2]

could be present in a strain lacking the active enzyme system responsible for the production of the benzo chromene class of cannabinoids. If anyone has a more complete list of phyto cannabiniods present in cannabis could you please post it up or link to it here thanks.

 

[mofeta]

Brenneisen's chapter from ElSohly's book is the most comprehensive paper on the chemical constituents of pot that I know of:

Chemistry and Analysis of Phytocannabinoids and Other Cannabis Constituents

The link is to the stand-alone chapter hosted on the Medical Genomics website.

 

[highonmt]

Brenneisen's chapter from ElSohly's book is the most comprehensive paper on the chemical constituents of pot that I know of:

Chemistry and Analysis of Phytocannabinoids and Other Cannabis Constituents

The link is to the stand-alone chapter hosted on the Medical Genomics website.

Thanks great link I will search further for reports of cb1 and 2 affinity in the various and sundry compounds. HM

 

[Chimera]

That's a really good point Highonmt. Classically, we referred to cannabinoids as compounds that are derived from and including CBG.

However, as you state we are considering terpenes as putative cannabinoids now, so the previous definition doesn't really make sense since as you say chemotype V plants that are deficient in CBG and its derivatives may still contain putative cannabinoids (ie terpenes).

This whole science is really very young, and we are tripping over ourselves now as it expands and we learn that our previous definitions are insufficient to tell a complete and accurate story.

Good post.

-Chimera

 

[paladin420]

Great post.. Please try to keep this as simple as possible for those of us in the field( as it where) ... Just white trash Tryin to help sick folk...

 

[highonmt]

Thanks for the kind words, if anyone here has access to scifinder or similar data base software please do some searching for cb1 and 2 affinity if I had access anymore I would do it myself but I threw the shackles of corporate America quite a while ago... I would also like to find info on any papers on the structure of the two receptors and any structural activity relationship [sar] information on the known cannabiniods.

 

[mofeta]

Thanks for the kind words, if anyone here has access to scifinder or similar data base software please do some searching for cb1 and 2 affinity if I had access anymore I would do it myself but I threw the shackles of corporate America quite a while ago... I would also like to find info on any papers on the structure of the two receptors and any structural activity relationship [sar] information on the known cannabiniods.

LOL! That is a tall order! This is one of the hottest subjects in neuropharmacology today, and there are important papers coming out every week it seems. As a chemist, you should have no problem reading these papers once you learn the specialized terms molecular neuropharmacologists use. The thing is is that there is A LOT to read.

Our understanding of the lipid neurotransmitters is still in it's infancy, but that is changing rapidly.

One thing I would point out is that it is becoming apparent that the CB1 and CB2 are just the tip of the iceberg. There are an increasing number of "orphan" GPCRs that are likely bound mainly by cannabinoids. Cannabinoids also exert their influence through mechanisms other than the GPCRs, like TPRV1 cation channel.(EDIT: forgot to mention that cannabinoids also bind the better known receptors, like 5HT etc. Also, here is a post I made about a watershed paper that shows how important cannabinoids are in modulating the more well-known neurotransmitters.)

As you know, most papers are behind a paywall, and subscriptions aren't cheap. There are, however, a lot of really good papers/books available in full-text for free.

You could do worse than start with these:

Cannabinoid pharmacology: the first 66 years-This is an overview by Pertwee, he is the man when it comes to cannabinoid pharmacology

The diverse CB1 and CB2 receptor pharmacology of
three plant cannabinoids: D9-tetrahydrocannabinol,
cannabidiol and D9-tetrahydrocannabivarin-another good one by Pertwee

Novel cannabinoid receptors-good one on cannabinoid receptors other than CB1 and CB2.

If you are just looking for Ki for various ligands of the well-known cannabinoid receptors, the PDSP database is real good (and free). Here is a link to the CB1 page:

PDSP CB1 binding affinity page

There are a lot more good resources free on the web, but the real world beckons, and I have to go now. I think the stuff above is a good start, I will post more later.

 

[highonmt]

Neuropharma research was my forte for a good while. Worked down in california for a huge mutinational reseach firm. We were working on TRI's which by the way we named in our lab. Dopamine is a tough one to work into the equation tho lol. I remember when we added the cannabiniod system to the huge recptor poster wall. These are going to be tough targets to characterize given the lipid soluble nature of the receptors. I appriciate the links I suspect there are allosteric binding sights on the recptor protien as well.
HM

LOL! That is a tall order! This is one of the hottest subjects in neuropharmacology today, and there are important papers coming out every week it seems. As a chemist, you should have no problem reading these papers once you learn the specialized terms molecular neuropharmacologists use. The thing is is that there is A LOT to read.

Our understanding of the lipid neurotransmitters is still in it's infancy, but that is changing rapidly.

One thing I would point out is that it is becoming apparent that the CB1 and CB2 are just the tip of the iceberg. There are an increasing number of "orphan" GPCRs that are likely bound mainly by cannabinoids. Cannabinoids also exert their influence through mechanisms other than the GPCRs, like TPRV1 cation channel.(EDIT: forgot to mention that cannabinoids also bind the better known receptors, like 5HT etc. Also, here is a post I made about a watershed paper that shows how important cannabinoids are in modulating the more well-known neurotransmitters.)

As you know, most papers are behind a paywall, and subscriptions aren't cheap. There are, however, a lot of really good papers/books available in full-text for free.

You could do worse than start with these:

Cannabinoid pharmacology: the first 66 years-This is an overview by Pertwee, he is the man when it comes to cannabinoid pharmacology

The diverse CB1 and CB2 receptor pharmacology of
three plant cannabinoids: D9-tetrahydrocannabinol,
cannabidiol and D9-tetrahydrocannabivarin-another good one by Pertwee

Novel cannabinoid receptors-good one on cannabinoid receptors other than CB1 and CB2.

If you are just looking for Ki for various ligands of the well-known cannabinoid receptors, the PDSP database is real good (and free). Here is a link to the CB1 page:

PDSP CB1 binding affinity page

There are a lot more good resources free on the web, but the real world beckons, and I have to go now. I think the stuff above is a good start, I will post more later.

 

[mofeta]

I suspect there are allosteric binding sights on the recptor protien as well.
HM

Here you go:

Allosteric Modulation of the Cannabinoid CB1 Receptor

 

[mofeta]

Neuropharma research was my forte for a good while. Worked down in california for a huge mutinational reseach firm. We were working on TRI's which by the way we named in our lab.

You should have an easy go at it with the cannabinoids then.

My interest in the TRIs has been rekindled recently, as they finally have some in clinical trials. I have an interest in anxiety/panic disorders, and how they relate to personality disorders. I am interested in the interplay between the locus coeruleus, hypothalamus, amygdala and the cingulate gyrus. I hope what we learn from the TRI clinical trials will help elucidate these relationships.

When I think of the firm you are referencing, I think of the name of the road it is on- it always reminds me of the science fiction I read as a kid! (if it's the place I'm thinking of in SD)

 

[mofeta]

Here is another you might like:

Phytocannabinoids beyond the Cannabis plant – do they exist?

 

[highonmt]

You should have an easy go at it with the cannabinoids then.

My interest in the TRIs has been rekindled recently, as they finally have some in clinical trials. I have an interest in anxiety/panic disorders, and how they relate to personality disorders. I am interested in the interplay between the locus coeruleus, hypothalamus, amygdala and the cingulate gyrus. I hope what we learn from the TRI clinical trials will help elucidate these relationships.

When I think of the firm you are referencing, I think of the name of the road it is on- it always reminds me of the science fiction I read as a kid! (if it's the place I'm thinking of in SD)

TRI's are really not that difficult other than the liabilities of dopamine re-uptake inhibition. Addiction risk is no longer acceptable in pharmaceuticals. The thing that makes tri research less difficult is the well characterized receptors. We have nice crystal structures of all three receptor sites complete with bound ligands. The lipophillic nature of the CB1 and 2 make them much much more difficult to characterize. That is why I was wondering about SAR papers that exist. With good SAR information you can at least look at energy minima of the active compounds and infer a few things about the active site. The allosteric sites on CB1 really explain to me the more 'powerful' effects of strains that do not have THC numbers high enough to justify the effect. Pre 98 bubba kush is a good example 10 percent THC and will cripple you where I have smoked reported 15 percent strains that seemed mild in comparison.
It will be interesting to see a large number of complete terpene and cannabinoid analysis linked to smoke reports, I think from this we as medical 'researchers' will be able to putatively identify allosteric ligands that up or down regulate cb1 and possibly cb2... this is the kind of home spun science that would make rupert shelldrake beam.
HM

 

[mofeta]

...the liabilities of dopamine re-uptake inhibition. Addiction risk is no longer acceptable in pharmaceuticals.

I'll say! It's similar to the opioid agonists. They work great for almost any mood/personality disorder- for a while. Then it stops working and the person is still mentally ill and a junkie.

The thing that makes tri research less difficult is the well characterized receptors. We have nice crystal structures of all three receptor sites complete with bound ligands. The lipophillic nature of the CB1 and 2 make them much much more difficult to characterize. That is why I was wondering about SAR papers that exist. With good SAR information you can at least look at energy minima of the active compounds and infer a few things about the active site.

There are scads of papers on SAR for cannabinoid receptor ligands. Enough to be overwhelming really. The structure of the receptors and their various sites is being revealed at an increasing pace.

The discovery of the synthetics really got things going. Then the "Spice" phenomenon accelerated this investigation.

The serendipitous discovery of the various indoles, pyrroles, indenes, etc as active is really interesting. These compounds were/are of interest as anti-inflammatory/anti-cancer agents. It turned out that they were "cannabinoids" sensu lato. Here is an relatively early example:

Structure-Activity Relationships of Indole- and Pyrrole-Derived
Cannabinoids

The investigations into the endocannabinoids has also been fruitful in this respect.

It will be interesting to see a large number of complete terpene and cannabinoid analysis linked to smoke reports, I think from this we as medical 'researchers' will be able to putatively identify allosteric ligands that up or down regulate cb1 and possibly cb2... this is the kind of home spun science that would make rupert shelldrake beam.
HM

I agree. The expertise of weed connoisseurs can be used to point the way for labwork.

 

[highonmt]

I enjoyed reading Wiley's paper but this is really a cursory study and does not have any molecular modeling studies etc which can really be of benefit when looking for compounds that are possible allosteric modulators of the cannabinoid receptors. I would even venture that amino alkyl indole cannabinioids like WIN 55,212 interact with completely different residues either within the active site or perhaps at an allosteric site on the recptors than the benzo chromene type or open chain poly ene type cannabinoids. The cannabiniod system really has a lot of promise for improving human health it will be interesting to see how the crystallographers fare in providing xray structures of the active site of the cannabinoid receptors.

 

[mofeta]

Sorry, I don't have a bookmarks folder for full-text 3D modeling papers. I don't know a whole lot about this subject either.

What I do know is that I see lots of papers where they use diffraction techniques, It didn't occur to me that it is harder to work with the lipid receptors than with monoamine receptors in this context, sometimes the obvious fails to strike me.

I have also gotten the impression that most 3D models of these receptors are generated more through numerical modeling, I think it is called QSAR.

I am also pretty sure that I have read that CB1 and CB2 are a lot like rhodopsin.

I have skimmed papers that describe various binding pockets and pharmacophores on the cannabinoid receptors, but I am out of my depth at this level of detail to tell the truth. I have what I call "Attention Surplus/Hyperactivity Disoder"- I am interested in everything. So I only have a certain amount of time I can devote to any one hobby. Maybe you could research out this aspect of cannabinoid pharmacology and condense it down for me and the other members. I would be grateful.

PS- I remembered I had this image, I can't remember where it's from but it is really cool. I don't know if it was generated directly with data from diffraction, or a hypothetical numerical model.

PPS: I see the url for the website that I got this from down in the left corner of the image

 

[highonmt]

Sorry, I don't have a bookmarks folder for full-text 3D modeling papers. I don't know a whole lot about this subject either.

What I do know is that I see lots of papers where they use diffraction techniques, It didn't occur to me that it is harder to work with the lipid receptors than with monoamine receptors in this context, sometimes the obvious fails to strike me.

I have also gotten the impression that most 3D models of these receptors are generated more through numerical modeling, I think it is called QSAR.

I am also pretty sure that I have read that CB1 and CB2 are a lot like rhodopsin.

I have skimmed papers that describe various binding pockets and pharmacophores on the cannabinoid receptors, but I am out of my depth at this level of detail to tell the truth. I have what I call "Attention Surplus/Hyperactivity Disoder"- I am interested in everything. So I only have a certain amount of time I can devote to any one hobby. Maybe you could research out this aspect of cannabinoid pharmacology and condense it down for me and the other members. I would be grateful.

PS- I remembered I had this image, I can't remember where it's from but it is really cool. I don't know if it was generated directly with data from diffraction, or a hypothetical numerical model.

PPS: I see the url for the website that I got this from down in the left corner of the image

That looks like a calculated model but it is the first I've seen. Thank you very much for posting this up. The picture is mainly just a lipid bi layer and the transmembrane helices are not detailed but it is at least a good start.

I wish I could take this on but I now have 2 jobs plus consulting, and no access to journals save what is on line. Life is pretty crazy now I have kids, I'm still recovering from brain surgery and radiation, sometimes it feels like I never will,but I finally seem to be catching up with time again. I will see if some old friends can use up a little university bandwidth and send me some better info. Thanks again for posting this up.
HM

 

[mofeta]

I'm still recovering from brain surgery and radiation, sometimes it feels like I never will,but I finally seem to be catching up with time again.

I didn't know that. I hope you make complete recovery soon.

I will see if some old friends can use up a little university bandwidth and send me some better info. Thanks again for posting this up.
HM

Right on. A lot of the best stuff is pay only. I don't have any subscriptions these days, but basically my whole family is in academia w/access to everything. The problem is that I drive them crazy with requests for stuff if I don't control myself. I have to pick the most important stuff to ask for every month, and a lot of times my cannabis hobby loses out to one of the others. I guess I should pony up and pay for one of the services.

I enjoy discussing this stuff with you, I hope you are able to continue.

I bet you will feel better soon.

mofeta

 

[highonmt]

I didn't know that. I hope you make complete recovery soon.



Right on. A lot of the best stuff is pay only. I don't have any subscriptions these days, but basically my whole family is in academia w/access to everything. The problem is that I drive them crazy with requests for stuff if I don't control myself. I have to pick the most important stuff to ask for every month, and a lot of times my cannabis hobby loses out to one of the others. I guess I should pony up and pay for one of the services.

I enjoy discussing this stuff with you, I hope you are able to continue.

I bet you will feel better soon.

mofeta

Oh I'm fine just a brain blister as my wife likes to tease me...too many years studying chemistry...I'm getting better all the time. Thanks for the well wishes.
HM