Thursday, March 28, 2013

The new synthetic cannabinoids on the block


Since approximately 2007, quinoline cannabinoid derivatives have been evaluated for cannabinoid receptor affinity.  A few studies have demonstrated a handful of compounds with the quinoline structure to be highly selective for the CB2 receptor over the CB1 receptor.
PB-22 and 5F-PB-22 are two emerging synthetic cannabinoid substances of this quinoline class.  They have been analytically confirmed as adulterants in herbal incense blends in the USA.




PB-22’s chemical name is 1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C23H22N2O2 and formula weight is 358.4 g/mol.  The chemical structure features an indole group, a pentyl alkyl chain, a carbonyl group and a 8-hydroxyquinoline moiety.
5F-PB-22’s chemical name is 1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C23H21FN2O2 and formula weight is 376.4 g/mol.  It features the same chemical structure as PB-22 with the exception of a single fluorine atom at the terminal carbon of the pentyl chain.
BB-22’s chemical name is 1-(cyclohexylmethyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C25H24N2O2 and formula weight is 384.5 g/mol.  It features the same chemical structure as PB-22 with the exception of the replacement of the pentyl alkyl chain with a cyclohexylmethyl moiety.
I am currently in the midwest traveling, so I thought I would look up these substances and see if they are controlled at the state level.  They are not controlled in any of the several midwestern states as schedule I drugs.  They are also not included in the updated list of controlled compounds in the legislation pending in any midwestern state.  In fact, I do not know of any location in the USA (state and/or federal) in which they are controlled explicitly.  It would also prove difficult to make these an analog case as they are significantly different (my scientific opinion) than JWH-018 or other controlled synthetic cannabinoids.   It is also of importance that these substances have no published in vitro or animal modeling data regarding their pharmacological activity at the receptor. 
Goodbye UR-144 and XLR-11.  Welcome the next wave of synthetic cannabinoids…the quinoline derivatives.  Meet the new boss, same as the old boss - more unknown than the preceding generations.
PS. Note reference 4 – not only the quinoline derivatives are listed, but also isoquinoline, quinoxaline, and quinazoline derivaties exist as well.
The cat and mouse games will continue!

References
1.    C Manera, V Benetti, MP Castelli et al. Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists. J Med Chem (2006) 49(20):  5947-5957.  PMID:  17004710
2.    C Manera, MG Cascio, V Benetti et al. New 1,8-naphthyridine and quinoline derivatives as CB2 selective agonists. Bioorg Med Chem Lett (2007) 17(23): 6505-6510.  PMID: 17942307
3.    R Saari, JC Torma, T Nevalainen. Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and quinazoline derivatives as CB2 receptor agonists. Bioorg Med Chem (2011) 19(2): 939-950. PMID: 21215643
4.    PG Baraldi, G Saponaro, AR Moorman et al. 7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as selective CB(2) cannabinoid receptor ligands: structural investigations around a novel class of full agonists. J Med Chem (2012) 55(14): 6608-6623.  PMID 22738271


9 comments:

  1. The recreational use of CB2 agonists is fascinating considering the dogma that's persisted for many years. Clearly there's abuse potential, but I've yet to see good publications explaining the pharmacological mechanisms behind it.

    The Italian group you cited in (4) is calling one of these highly-CB2-specific (1000x vs CB1) quinolines "MT178", and have just published in this month's Pain showing significant antinociceptive effects. Rather interesting results IMO (Substance P release, NF-kB significantly inhibited, etc). I'm sure we'll be seeing more of this soon...

    PMID - 23518609

    ReplyDelete
  2. Thanks for that link. I'll have to look it up.

    I think the important thing to remember is that most of these substances showing up in herbal blend products are selective for CB2, but do retain some activity at CB1 - some compounds more than others.

    JWH-018: Ki at CB1 is 9 nM; Ki at CB2 is 2.94 nM. JWH-018 is actually 3 times more selective for CB2 than CB1, which is something many people forget.

    Look at 3 of the tetramethylcyclopropyl substances:

    A796,260: Ki at CB1 is 945 nM; Ki at CB2 is 4.6 nM.

    A834,735: Ki at CB1 is 12 nM; Ki at CB2 is 0.21 nM.

    UR-144: Ki at CB1 is 150 nM; Ki at CB2 is 1.8 nM.

    All are selective for CB2 over CB1, but all do have binding activity at CB1, with A834,735 being the most potent.

    UR-144 became very, very popular in 2012. One reason was because it evaded legislation/laws, but another reason may be because, even though it was labeled as a CB2 agonist, it seems as if it still retained enough activity at CB1 to produce a psychoactive effect.

    Also, I think what is in play is the dosing. Keep in mind that these substances are in unknown dosages in these products. A substance that has very little activity at CB1 will probably show no effects at very low to low dosages, but what happens if the dosage increased substantially?

    ReplyDelete
  3. For reference MT178 is referenced with a Ki of >10,000nM for CB1 and 7.8nM for CB2.

    So do you think the high CB2:CB1 Ki ratio compounds you've been seeing are more a product of a lack of availability of more strongly-biased CB1 compounds? Or could it be that there's some CB2-related mechanism (perhaps cross-talk with other receptors or downstream 2nd messenger signalling, etc) that these human guinea pigs find alluring? Just strikes me as odd given the literature that exists on the psychopharmacology of these compounds... but I've no 1st-hand experience with these things.

    ReplyDelete
  4. About a year ago I purchased 5 grams of 5F-AKB48 from China. Fearing the problems overdose, I mixed the 5 grams with 8 ounces of 190 proof alcohol and applied it to a pound of Damiana. Since I hadn't been a regular smoker for decades, though it was initially OK, after awhile it proved to be to weak. I doubled the next batch and it was better, but once again, after a month or so of usage, it was too weak. I'm about to make my third batch and I'm looking for some guidelines. Are there any?

    ReplyDelete
  5. It was wondering if I could use this write-up on my other website, I will link it back to your website though. Great Thanks.
    Herbal Potpourri

    ReplyDelete
  6. spice4fun.com has way better aroma

    ReplyDelete
  7. this is really very helpful article. I go through this site really very nice information.thank for sharing such a nice information weed incense

    ReplyDelete
  8. Hey I just want to appreciate your ability to work. You have set an example for us by posting such an informative post. Great work.

    buy k2 online

    ReplyDelete
  9. Wow, absolutely fantastic blog. I am very glad to have such useful information. Thanks. Fashion Clothing

    ReplyDelete