JWH-015

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JWH-015
JWH-015.svg
Legal status
Legal status
Identifiers
  • (2-Methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.161.912 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H21NO
Molar mass 327.427 g·mol−1
3D model (JSmol)
  • CCCN1C(=C(C2=CC=CC=C21)C(=O)C3=CC=CC4=CC=CC=C43)C
  • InChI=1S/C23H21NO/c1-3-15-24-16(2)22(20-12-6-7-14-21(20)24)23(25)19-13-8-10-17-9-4-5-11-18(17)19/h4-14H,3,15H2,1-2H3 X mark.svgN
  • Key:LJSBBBWQTLXQEN-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

JWH-015 is a chemical from the naphthoylindole family that acts as a subtype-selective cannabinoid agonist. Its affinity for CB2 receptors is 13.8 nM, while its affinity for CB1 is 383 nM, meaning that it binds almost 28 times more strongly to CB2 than to CB1. [1] However, it still displays some CB1 activity, and in some model systems can be very potent and efficacious at activating CB1 receptors, [2] and therefore it is not as selective as newer drugs such as JWH-133. [3] It has been shown to possess immunomodulatory effects, [4] [5] and CB2 agonists may be useful in the treatment of pain and inflammation. [6] [7] It was discovered and named after John W. Huffman.

Contents

Metabolism

JWH-015 has been shown in vitro to be metabolized primarily by hydroxylation and N-dealkylation, and also by epoxidation of the naphthalene ring, [8] similar to the metabolic pathways seen for other aminoalkylindole cannabinoids such as WIN 55,212-2. [9] Epoxidation of polycyclic aromatic hydrocarbons (see for example benzo(a)pyrene toxicity) can produce carcinogenic metabolites, although there is no evidence to show that JWH-015 or other aminoalkylindole cannabinoids are actually carcinogenic in vivo. JWH-015 may signal certain cancers to shrink through a process called apoptosis. [10]

In the United States, all CB1 receptor agonists of the 3-(1-naphthoyl)indole class such as JWH-015 are Schedule I Controlled Substances. [11]

As of October 2015 JWH-015 is a controlled substance in China. [12]

JWH-015 has been classified under the German BtMG as Anlage II. [13]

Related Research Articles

<span class="mw-page-title-main">WIN 55,212-2</span> Chemical compound

WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.

<span class="mw-page-title-main">JWH-081</span> Chemical compound

JWH-081 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. With a Ki of 1.2nM it is fairly selective for the CB1 subtype, its affinity at this subtype is measured at approximately 10x the affinity at CB2(12.4nM). It was discovered by and named after John W. Huffman.

<span class="mw-page-title-main">JWH-203</span> Chemical compound

JWH-203 (1-pentyl-3-(2-chlorophenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family that acts as a cannabinoid agonist with approximately equal affinity at both the CB1 and CB2 receptors, having a Ki of 8.0 nM at CB1 and 7.0 nM at CB2. It was originally discovered by, and named after, John W. Huffman, but has subsequently been sold without his permission as an ingredient of synthetic cannabis smoking blends. Similar to the related 2'-methoxy compound JWH-250, the 2'-bromo compound JWH-249, and the 2'-methyl compound JWH-251, JWH-203 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds, and has the strongest in vitro binding affinity for the cannabinoid receptors of any compound in the phenylacetyl group.

<span class="mw-page-title-main">JWH-210</span> Chemical compound

JWH-210 is an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both the CB1 and CB2 receptors, with Ki values of 0.46 nM at CB1 and 0.69 nM at CB2. It is one of the most potent 4-substituted naphthoyl derivatives in the naphthoylindole series, having a higher binding affinity (i.e. lower Ki) at CB1 than both its 4-methyl and 4-n-propyl homologues JWH-122 (CB1 Ki 0.69 nM) and JWH-182 (CB1 Ki 0.65 nM) respectively, and than the 4-methoxy compound JWH-081 (CB1 Ki 1.2 nM). It was discovered by and named after John W. Huffman.

<span class="mw-page-title-main">JWH-007</span> Chemical compound

JWH-007 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It was first reported in 1994 by a group including the noted cannabinoid chemist John W. Huffman. It was the most active of the first group of N-alkyl naphoylindoles discovered by the team led by John W Huffman, several years after the family was initially described with the discovery of the N-morpholinylethyl compounds pravadoline (WIN 48,098), JWH-200 (WIN 55,225) and WIN 55,212-2 by the Sterling Winthrop group. Several other N-alkyl substituents were found to be active by Huffman's team including the n-butyl, n-hexyl, 2-heptyl, and cyclohexylethyl groups, but it was subsequently determined that the 2-methyl group on the indole ring is not required for CB1 binding, and tends to increase affinity for CB2 instead. Consequently, the 2-desmethyl derivative of JWH-007, JWH-018, has slightly higher binding affinity for CB1, with an optimum binding of 9.00 nM at CB1 and 2.94 nM at CB2, and JWH-007 displayed optimum binding of 9.50 nM at CB1 and 2.94 nM at CB2.

<span class="mw-page-title-main">JWH-019</span> Chemical compound

JWH-019 is an analgesic chemical from the naphthoylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is the N-hexyl homolog of the more common synthetic cannabinoid compound JWH-018. Unlike the butyl homolog JWH-073, which is several times weaker than JWH-018, the hexyl homolog is only slightly less potent, although extending the chain one carbon longer to the heptyl homolog JWH-020 results in dramatic loss of activity. These results show that the optimum side chain length for CB1 binding in the naphthoylindole series is the five-carbon pentyl chain, shorter than in the classical cannabinoids where a seven-carbon heptyl chain produces the most potent compounds. This difference is thought to reflect a slightly different binding conformation adopted by the naphthoylindole compounds as compared to the classical cannabinoids, and may be useful in characterizing the active site of the CB1 and CB2 receptors.

<span class="mw-page-title-main">JWH-167</span> Chemical compound

JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 1.75 times selectivity for CB1 with a Ki of 90 nM ± 17 and 159 nM ± 14 at CB2. Similar to the related 2'-methoxy compound JWH-250, and the 2'-chloro compound JWH-203, JWH-167 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds.

<span class="mw-page-title-main">JWH-249</span> Chemical compound

JWH-249 (1-pentyl-3-(2-bromophenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 2.4 times selectivity for CB1 with a Ki of 8.4 ± 1.8 nM and 20 ± 2 nM at CB2. Similar to the related 2'-methoxy compound JWH-250, the 2'-chloro compound JWH-203, and the 2'-methyl compound JWH-251, JWH-249 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds.

<span class="mw-page-title-main">A-834,735</span> Chemical compound

A-834,735 is a drug developed by Abbott Laboratories that acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors, with a Ki of 12 nM at CB1 and 0.21 nM at CB2. Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids with the 3-tetramethylcyclopropylmethanone group of A-834,735 and related compounds imparts significant selectivity for CB2, with most compounds from this group found to be highly selective CB2 agonists with little affinity for CB1. However, low nanomolar CB1 binding affinity is retained with certain heterocyclic 1-position substituents such as (N-methylpiperidin-2-yl)methyl (cf. AM-1220, AM-1248), or the (tetrahydropyran-4-yl)methyl substituent of A-834,735, resulting in compounds that still show significant affinity and efficacy at both receptors despite being CB2 selective overall.

<span class="mw-page-title-main">A-796,260</span> Chemical compound

A-796,260 is a drug developed by Abbott Laboratories that acts as a potent and selective cannabinoid CB2 receptor agonist. Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids with the 3-tetramethylcyclopropylmethanone group, imparts significant selectivity for CB2, and A-796,260 was found to be a highly selective CB2 agonist with little affinity for CB1, having a CB2Ki of 4.6 nM vs 945 nM at CB1. It has potent analgesic and anti-inflammatory actions in animal models, being especially effective in models of neuropathic pain, but without producing cannabis-like behavioral effects.

<span class="mw-page-title-main">AM-630</span> Chemical compound

AM-630 (6-Iodopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2, with a Ki of 32.1 nM at CB2 and 165x selectivity over CB1, at which it acted as a weak partial agonist. It is used in the study of CB2 mediated responses and has been used to investigate the possible role of CB2 receptors in the brain. AM-630 is significant as one of the first indole derived cannabinoid ligands substituted on the 6-position of the indole ring, a position that has subsequently been found to be important in determining affinity and efficacy at both the CB1 and CB2 receptors, and has led to the development of many related derivatives.

<span class="mw-page-title-main">AM-2233</span> Chemical compound

AM-2233 is a drug that acts as a highly potent full agonist for the cannabinoid receptors, with a Ki of 1.8 nM at CB1 and 2.2 nM at CB2 as the active (R) enantiomer. It was developed as a selective radioligand for the cannabinoid receptors and has been used as its 131I derivative for mapping the distribution of the CB1 receptor in the brain. AM-2233 was found to fully substitute for THC in rats, with a potency lower than that of JWH-018 but higher than WIN 55,212-2.

<span class="mw-page-title-main">JWH-251</span> Chemical compound

JWH-251 (1-pentyl-3-(2-methylphenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about five times selectivity for CB1 with a Ki of 29 nM and 146 nM at CB2. Similar to the related 2'-methoxy compound JWH-250, the 2'-chloro compound JWH-203, and the 2'-bromo compound JWH-249, JWH-251 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds.

<span class="mw-page-title-main">JWH-424</span> Chemical compound

JWH-424 is a drug from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors, but with moderate selectivity for CB2, having a Ki of 5.44nM at CB2 vs 20.9 nM at CB1. The heavier 8-iodo analogue is even more CB2 selective, with its 2-methyl derivative having 40 times selectivity for CB2. However the 1-propyl homologues in this series showed much lower affinity at both receptors, reflecting a generally reduced affinity for the 8-substituted naphthoylindoles overall.

<span class="mw-page-title-main">AM-1235</span> Chemical compound

AM-1235 (1-(5-fluoropentyl)-3-(naphthalen-1-oyl)-6-nitroindole) is a drug that acts as a potent and reasonably selective agonist for the cannabinoid receptor CB1.

<span class="mw-page-title-main">AM-1220</span> Chemical compound

AM-1220 is a drug that acts as a potent and moderately selective agonist for the cannabinoid receptor CB1, with around 19 times selectivity for CB1 over the related CB2 receptor. It was originally invented in the early 1990s by a team led by Thomas D'Ambra at Sterling Winthrop, but has subsequently been researched by many others, most notably the team led by Alexandros Makriyannis at the University of Connecticut. The (piperidin-2-yl)methyl side chain of AM-1220 contains a stereocenter, so there are two enantiomers with quite different potency, the (R)-enantiomer having a Ki of 0.27 nM at CB1 while the (S)-enantiomer has a much weaker Ki of 217 nM.

<span class="mw-page-title-main">UR-144</span> Chemical compound

UR-144 (TMCP-018, KM-X1, MN-001, YX-17) is a drug invented by Abbott Laboratories, that acts as a selective full agonist of the peripheral cannabinoid receptor CB2, but with much lower affinity for the psychoactive CB1 receptor.

<span class="mw-page-title-main">JWH-047</span> Chemical compound

JWH-047 is a selective cannabinoid ligand that binds to both CB1 and CB2. It has a bindining affinity of Ki = 0.9 nM for the CB2 subtype, and more than 65 times selectivity over the CB1.

<span class="mw-page-title-main">JWH-048</span> Chemical compound

JWH-048 is a selective cannabinoid ligand, with a bindining affinity of Ki = 0.5 ± 0.1 nM for the CB2 subtype, and more than 22 times selectivity over the CB1.

References

  1. Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, et al. (August 2000). "Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2)receptor binding". Drug and Alcohol Dependence. 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID   10940540.
  2. Murataeva N, Mackie K, Straiker A (November 2012). "The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons". Pharmacological Research. 66 (5): 437–442. doi:10.1016/j.phrs.2012.08.002. PMC   3601544 . PMID   22921769.
  3. Marriott KS, Huffman JW (2008). "Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor". Current Topics in Medicinal Chemistry. 8 (3): 187–204. doi:10.2174/156802608783498014. PMID   18289088.
  4. Ghosh S, Preet A, Groopman JE, Ganju RK (July 2006). "Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes". Molecular Immunology. 43 (14): 2169–2179. doi:10.1016/j.molimm.2006.01.005. PMID   16503355.
  5. Montecucco F, Burger F, Mach F, Steffens S (March 2008). "CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways". American Journal of Physiology. Heart and Circulatory Physiology. 294 (3): H1145–H1155. doi:10.1152/ajpheart.01328.2007. PMID   18178718. S2CID   5896815.
  6. Balter MB, Uhlenhuth EH (1992). "Prescribing and use of benzodiazepines: an epidemiologic perspective". Journal of Psychoactive Drugs. 24 (1): 63–64. doi:10.1080/02791072.1992.10471620. PMID   1352348.
  7. Romero-Sandoval A, Eisenach JC (April 2007). "Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision". Anesthesiology. 106 (4): 787–794. doi: 10.1097/01.anes.0000264765.33673.6c . PMID   17413917.
  8. Zhang Q, Ma P, Cole RB, Wang G (November 2006). "Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS". Analytical and Bioanalytical Chemistry. 386 (5): 1345–1355. doi:10.1007/s00216-006-0717-6. PMID   16955257. S2CID   9116612.
  9. Zhang Q, Ma P, Iszard M, Cole RB, Wang W, Wang G (October 2002). "In vitro metabolism of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist". Drug Metabolism and Disposition. 30 (10): 1077–1086. doi:10.1124/dmd.30.10.1077. PMID   12228183. S2CID   10848076.
  10. Olea-Herrero N, Vara D, Malagarie-Cazenave S, Díaz-Laviada I (September 2009). "Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: involvement of CB2". British Journal of Cancer. 101 (6): 940–950. doi:10.1038/sj.bjc.6605248. PMC   2743360 . PMID   19690545.
  11. 21 U.S.C.   § 812 : Schedules of controlled substances
  12. "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" [Notice on Issuing the Measures for the Listing and Control of Non-Medicinal Narcotic Drugs and Psychotropic Substances] (in Chinese). China Food and Drug Administration. 27 September 2015. Archived from the original on 1 October 2015. Retrieved 1 October 2015.
  13. "Stoffe gem. Anlagen zum BtMG" . Retrieved 2024-11-23.