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Phenylacetylindoles

The alkylated napthoylindoles were the first synthetic cannabinoids cheap and potent enough to make real noise on the recreational drug market. Concern was initially raised about metabolism of the naphthalene ring and resulting carcinogenic risk, which turned out to be validated (abstract O43) although perhaps initially overstated as it lies within a similar risk envelope as cigarettes. Compounds have now been produced that replace the naphthalene ring with a phenylacetyl group. These represent a new and unique class of synthetic cannabinoids, with applications as both replacements for banned cannabinoids and use as a possibly healthier alternative for informed users. Without substitution the structure is much less potent than JWH-018, but various substitutions at the 2, 3, and 4-position have been attempted. The 2-position substitutions demonstrate the highest potency as a class, and are outlined here.

JWH-167 (CB1 K_i = 90 ± 17 nM, CB2 K_i = 159 ± 14 nM) is shown here with JWH-018 and its naphthalene group in a light grey underlay for reference. Without any substitutions this base phenylacetylindole is not potent enough for sale on the recreational drug market, as it is roughly a tenth as potent as JWH-018 as measured by binding affinity.

JWH-251 (CB1 K_i = 29 ± 3 nM, CB2 K_i = 146 ± 36 nM). A methyl group at the 2-position increases potency, but binding affinities seem to be too weak for practical sale. This is contrasted with the facts that JWH-251 was found to be a component of certain Japanese “herbal smoke” blends and limited reports indicate this to be of somewhat similar qualitative potency to JWH-250. Time will tell if this compound will remain on the edge of the market or gain popularity.

JWH-250 (CB1 K_i = 11 ± 2 nM, CB2 K_i = 33 ± 2 nM). Currently the most popular phenylacetylindole. The 2-methoxy substitution produces a compound that is qualitatively slightly less potent than JWH-018, but produces a much more pleasant effect in higher dose ranges. As such, this compound has found favor with those who prefer a stronger cannabinoid experience without the near-certainty of anxiety in higher doses that JWH-018 was known to cause.

JWH-311 (CB1 K_i = 23 ± 2 nM, CB2 K_i = 39 ± 3 nM). Fluorine substitution provides the least potent outcome of the three halogens Huffman explored. Not widely available or tested.

JWH-203 (CB1 K_i = 8.0 ± 0.9 nM, CB2 K_i = 7.0 ± 1.3 nM). The most potent halogen substitution, and one of the most potent phenylacetylindoles along with JWH-250. Currently available for sale, but not widely explored.

JWH-249 (CB1 K_i = 8.4 ± 1.8 nM, CB2 K_i = 20 ± 2 nM). Slightly less potent than JWH-203, with a lower CB2 affinity that may be associated with reduced anxiety effects. Not widely available for sale, but could be waiting in the wings if JWH-203 takes off and is scheduled.

John W. Huffman, P. V. Szklennik, A. Almond, K. Bushell, D. E. Selley, H. He, M. P. Cassidy, J. L. Wiley, B. R. Martin, 1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles, Bioorganic & Medicinal Chemistry Letters, Volume 15, Issue 18, 15 September 2005, Pages 4110-4113, ISSN 0960-894X, DOI: 10.1016/j.bmcl.2005.06.008.

Burn it up, Thoughts on JWH-18 carcinogenicity, 01-05-2010, 02:22, Bluelight > Drug Discussion > Advanced Drug Discussion.

Synthetic Cannabinoids: JWH-018 4-Alkyl Substitutions

Ah, JWH-018. Trivial to synthesize, highly potent, and a formerly legal substitute for the world’s most popular contraband drug. No wonder it reached the heights of popularity it did, and no wonder that labs are currently scrambling to replace it. And just like in corporate pharmacology, small substitutions can create not only a new compound, but a new cash cow free of previous legal restraints.

So let’s look at the naphthyl ring of JWH-018 in particular, and number our possible substitution sites for clarity. We could try many approaches at many positions, but suppose we limit ourselves to the 4-position. The halogens are a possibility (JWH-398 can be thought of JWH-018 with a chlorine substituted here), but let’s try some alkyl chains and see if they come up winners.

For reference, JWH-018 has binding affinities of 9.00 nM at CB1 and 2.94 nM at CB2. If we were a lab, we’d be looking for higher potency compounds (lower binding affinities) since increased attention from law enforcement means the only rational choice is to pack as much punch as you can in the smallest package for transport. It might be nice to try to search for compounds with the most pleasant effects, but that seems to be rather idealistic in the cold light of this new day.

JWH-122 (CB1 K_i = 0.69 nM, CB2 K_i = 1.20 nM) Our first try, and things are looking good. A drastic increase in potency based on binding affinities, slightly smaller doses compared to JWH-018, and similar effects. Duration also appears to increase with this substitution, making it an apparent winner all around.
JWH-210 (CB1 K_i = 0.46 nM, CB2 K_i = 0.69 nM) Increasing the alkyl chain length by a carbon appears to produce little drastic change. A similar duration to JWH-122, with perhaps a slight decrease in potency. A stimulating and slightly trippy headspace.
JWH-182 (CB1 K_i = 0.65nM, CB2 K_i = 1.10 nM) Should be quite potent based on binding affinities, but is not widely distributed in the marketplace. Perhaps perceived qualitative potency in human subjects decreases as the 4-alkyl chain length increases as seen in the move from JWH-122 to JWH-210, making this compound not economical to produce at this point in time.

Synthetic Cannabinoids: JWH-018 Replacements

On November 24, 2010, the DEA used its emergency scheduling authority to temporarily control JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol, synthetic cannabinoids used as cannabis substitutes. If history is any guide, this tempory control will soon become permanent. The major motivations for this action appeared to be twofold. First, use among members of the military had become increasingly prevalent as these compounds produced metabolites that did not flag typical drug tests. Secondly, the high potency and full agonism of certain compounds (particularly JWH-018) could lead to states of anxiety in higher doses. While a temporary mental state and not reflective of any physical toxicity, hospitals began reporting an increase in admissions and emergency calls from primarily inexperienced and younger users in the midst of a wigout. Despite a complete lack of quantifiable mental or physical harm, this led to media demonization as a “dangeous drug available to teens”.

So the DEA intervened, but there’s just one problem. The synthetic cannabinoids emergency scheduled are a tiny fraction of literally thousands of related compounds known to science - with more being discovered every day. So what are some of the cannabinoids currently on the market that slide in under the radar?

JWH-018 (CB1 K_i = 9.00 nM, CB2 K_i = 2.94 nM) The most famous alkylated naphthoylindole, doomed to criminalization in the United States, and included here as a structural reference.
JWH-019 (CB1 K_i = 9.80 nM, CB2 K_i = 5.55 nM) Poor JWH-019. An alkylated naphthoylindole just like its butyl (JWH-073) and pentyl (JWH-018) brothers, they rose to fame while it languished in obscurity. A less anxiety prone and more cerebral headspace combined with a marginal decrease in potency relative to JWH-018 could lead to the last still-legal homologue of the family finally getting its dues.
JWH-081 (CB1 K_i = 1.20 nM, CB2 K_i = 12.4 nM) If we look at the structure of JWH-081, we can see that it is very similar to JWH-018 with the exception of the methoxy group. Unlike JWH-018 however, it is more selective for the CB1 receptor which appears to be correlated with reduced anxiety (like JWH-073). A less trippy headspace with more physical stoning effects, and mild euphoria.
JWH-250 (CB1 K_i = 11 nM, CB2 K_i = 33 nM) Replace the notorious napthalene ring of JWH-018 with a 2′-methoxyphenylacetyl group and you get JWH-250, a rising star. Unlike other synthetic cannabinoids which produce a more indica-style headspace, JWH-250 produces an effect somewhat similar to JWH-018 with a clear, soaring, sativa charactered stone.
RCS-4 (BTM-4, SR-19) (CB1 K_i = ?? nM, CB2 K_i = ?? nM) With a structure reminiscent of JWH-081 if we chopped its napthyl in half to produce a phenyl group, this synthetic cannabinoid has similar potency and effects to JWH-018, all allegedly without legal issues or the infamous JWH “fear”. Interestingly enough this seems to be the result of independent research seeking new psychoactive (and profitable) cannabinoids, and not simply someone pinching from academic journal articles. Prohibition made the production of these cannabinoids a huge cash cow, and now a self-sustaining independent industry with very credible players has been born.
AM-694 (CB1 K_i = 0.08 nM, CB2 K_i = 1.44 nM) A hyperpotent cannabinoid based on CB1 binding affinity, with a fluorine on the end of the pentyl chain in an apparent attempt to increase duration of effect. This raised some eyebrows when it first appeared with concerns about possible metabolism to toxic fluoroacetate. Luckily it appears that the odd-numbered (pentyl) chain means that the less toxic 3-fluoropropanoic acid will likely be produced instead. The choice of this compound for wide distribution rather than other alternatives raises questions, as the emphasis on duration and potency seem to reveal a focus on profit rather than quality of headspace.

This should not be considered anywhere near a complete list of compounds currently available in the marketplace, and is an even tinier slice of the vast number known to produce pleasurable psychoactive effects. It seems unlikely that a blanket approach based on criminalization will be practical, as a large number of related compounds have demonstrated breakthrough benefit in treating afflictions such as Alzheimer’s and cancer. There is simply too much money to be made with these new medicines that would be caught in the net, and legislators are aware of this.

What seems more likely is an uneasy truce between synthetic cannabinoid producers and the DEA based on certain criteria. If the producers are sensible enough to avoid explicit sales to military personnel and teens resulting in decreased media attention, they will likely be ignored. Synthetic cannabinoids preparations sold on a retail level (“herbal incence” products) will likely be seized for “investigation” regardless of the legality of the active ingredient, as inventory tied up in evidence lockers will result in cost pressures almost as effective as an actual ban. Existing distributors are likely to move toward larger scale sale of explicitly unscheduled cannabinoids, allowing greed to motivate new smaller players to move into the now excessive scrutiny of retail level distribution.

Synthetic Cannabinoids: The Alkylated Naphthoylindoles

There are a huge variety of synthetic cannabinoids possible, including variations on THC and other natural cannabinoids, the CP series created by Pfizer in the 1970s but never brought to market, anti-Alzheimer’s treatment HU-210, and aminoalkylindole derivatives like WIN 55,212-2. But the most popular and prevalent synthetic cannabinoids in today’s recreational drug market are a subset of what are colloquially known as “JWHs”, after the researcher who completed a large body of work on them, John W. Huffman. There are several hundred of these compounds, named in the format JWH-001 and up. Some of the first compounds in this long list to be diverted to the recreational drug market are certain alkylated naphthoylindoles, which also happen to be very easy to synthesize. Have you used “herbal incense”, “Spice”, “K2”, or any of the other cannabis substitutes that have been popping up lately? A safe bet is that they’re an inactive herbal carrier with these synthetic cannabinoids dissolved in a solvent sprayed on top.

Synthetic cannabinoids sold in this manner drive a large and profitable industry, a strange bastard child of prohibition that would simply not exist if the sale of cannabis was regulated. While a small subset of informed drug users would likely still create demand for pure versions of these products, “incense” consumption would be effectively zero if the general population had access to quality cannabis and did not have to worry about metabolic products being tested for.

Imagine the state of the synthetic cannabis industry a few years ago. There have been whispers of some interesting cannabinoids being developed by academics for medical use and research. But how is it possible to tell which of these might substitute for THC in recreational users? Let’s investigate the binding affinity, a measure of how well a compound binds to a receptor. We can use K_i values to do this, which measure how concentrated the compound must be in order for it to have an equal chance of being bound to a receptor or not. Lower values mean high potency as only a small amount of compound is required, while higher values indicate lower potency. While having similar binding affinities doesn’t always mean similar recreational effects, it can certainly help narrow the field. Let’s see how the first seven alkylated naphthoylindoles stack up against THC.

Compound	CB1 K_i (nM)	CB2 K_i (nM)	Image
THC (reference)	40.7 ± 1.7	36.4 ± 10
JWH-070 (methyl)	>10000	>10000
JWH-071 (ethyl)	1340 ± 123	2940 ± 852
JWH-072 (n-propyl)	1050 ± 55.0	170 ± 54.0
JWH-073 (n-butyl)	8.90 ± 1.80	38.0 ± 24.0
JWH-018 (n-pentyl)	9.00 ± 5.00	2.94 ± 2.65
JWH-019 (n-hexyl)	9.80 ± 2.00	5.55 ± 2.00
JWH-020 (n-heptyl)	128 ± 17.0	205 ± 20

The shorter alkyl chain lengths of JWH-070 (ethyl) and JWH-071 (methyl) show negligible activity. As we move to the propyl chain of JWH-072 we see little change in CB1 binding affinity but CB2 affinity increases almost 15 times. JWH-073 and its butyl chain are a bit more promising, with higher affinity for CB1 and a similar affinity for CB2 compared to THC. JWH-018 (pentyl) and JWH-019 (hexyl) stand out, with higher potency at both receptors than THC itself. So far so good, but as we increase the chain length in JWH-020 (heptyl) our streak ends, as we see a a 13 fold decrease in binding afﬁnity at the CB1 receptor and a 40 fold reduction at the CB2 receptor.

Activity appears to peak around the five carbon pentyl chain in these naphthoylindoles, as opposed to the classical cannabinoids which peak at the seven carbon heptyl chain. Judging from binding affinities It looks like JWH-073, JWH-018, and JWH-019 would be the best bets - so did any of them pan out?

JWH-018 is likely the world’s most popular synthetic cannabinoid, and was one of the first introduced for wide sale. It entered the public psyche in late 2008 when German company THC-Pharm identified it as a primary ingredient in the “Spice” herbal smoke blend. Quickly outlawed in Germany and several other European countries in early 2009, it has since gained popularity in other markets including the US. Active in smoked dosages of only a few milligrams, tolerance builds quickly revealing a dirty secret relative to natural cannabis. JWH-018 is a single compound active as a full cannabinoid agonist, while cannabis acts as a mixture of many phytocannabinoids including partial agonists and antagonists. This complex balancing act provides a safety net that JWH-018 lacks, as the synthetic compound can activate cannabinoid receptors in a far more specific and potent manner. For instance, GABA may be inhibited far more effectively than natural cannabis, leading to severe anxiety and reduced seizure threshold at high doses. This may be the origin of the infamous “fear” JWH-018 is known to induce in overdose.

JWH-073 is not as potent as JWH-018, but has arguably a more pleasant high with less anxious effects. After JWH-018 was outlawed in Germany, a seizure and analysis of a new batch of Spice shipped only 4 weeks after the ban showed that the manufacturers had quickly switched active ingredients to the uncontrolled JWH-073.

JWH-019 has not reached the same fame as the others likely due to timing and distribution rather than any real shortcomings. It was introduced to a more saturated market along with many other competing synthetic cannabinoids after JWH-018 and JWH-073 were banned in some areas. This is likely to represent the new normal, as a wide number of these compounds targeting various recreational effects pop in and out of the market depending on economic and legal factors.

Mie Mie Aung, Graeme Griffin, John W Huffman, Ming-Jung Wu, Cheryl Keel, Bin Yang, Vincent M Showalter, Mary E Abood, Billy R Martin, Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding, Drug and Alcohol Dependence, Volume 60, Issue 2, 1 August 2000, Pages 133-140, ISSN 0376-8716, DOI: 10.1016/S0376-8716(99)00152-0.

RT @Erowid: Uruguay senate just approved regulating production, sale & consumption of cannabis. Needs pres. signature. http://t.co/nwObNqSF…

rational exploration of the underground

Phenylacetylindoles

Synthetic Cannabinoids: JWH-018 4-Alkyl Substitutions

Synthetic Cannabinoids: JWH-018 Replacements

Synthetic Cannabinoids: The Alkylated Naphthoylindoles

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