Org 28312

Last updated
Org 28312
Org 28312 Structure.svg
Identifiers
  • [1-(cyclohexylmethyl)-7-methoxyindol-3-yl]-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)methanone
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C24H35N3O2
Molar mass 397.563 g·mol−1
3D model (JSmol)
  • COc2cccc1c2n(CC4CCCCC4)cc1C(=O)N(CC3C)CC(C)N3C
  • InChI=1S/C24H35N3O2/c1-17-13-27(14-18(2)25(17)3)24(28)21-16-26(15-19-9-6-5-7-10-19)23-20(21)11-8-12-22(23)29-4/h8,11-12,16-19H,5-7,9-10,13-15H2,1-4H3/t17-,18+ Yes check.svgY
  • Key:DMYGECJTVMCGEP-HDICACEKSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Org 28312 is a drug developed by Organon International which acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors. It was developed with the aim of finding a water-soluble cannabinoid agonist suitable for intravenous use as an analgesic, but did not proceed to human trials, with the related compound Org 28611 chosen instead due to its better penetration into the brain. [1] The structure-activity relationships of these compounds have subsequently been investigated further leading to the development of a number of more potent analogues, derived by cyclisation around the indole or piperazine rings. [2] [3]

See also

Related Research Articles

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AMG-3 (part of the AM cannabinoid series) is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8-THC substituted with a dithiolane group on the 3-position side chain. AMG-3 is a potent agonist at both CB1 and CB2 receptors with a Ki of 0.32 nM at CB1 and 0.52 nM at CB2, and its particularly high binding affinity has led to it being used as a template for further structural development of novel cannabinoid drugs. It has sedative and analgesic effects, with analgesia lasting for up to 36 hours after administration.

A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol (CBD), a naturally occurring cannabinoid and a non-competitive CB1/CB2 receptor antagonist, as well as Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.

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

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

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<span class="mw-page-title-main">SER-601</span> Chemical compound

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

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<span class="mw-page-title-main">Org 28611</span> Chemical compound

Org 28611 (SCH-900,111) is a drug developed by Organon International which acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors. It was developed with the aim of finding a water-soluble cannabinoid agonist suitable for intravenous use as an analgesic, and while it achieved this aim and has progressed as far as Phase II clinical trials in humans as both a sedative and an analgesic, results against the comparison drugs (midazolam and morphine respectively) were not particularly favourable in initial testing.

<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">JWH-302</span> Chemical compound

JWH-302 (1-pentyl-3-(3-methoxyphenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist with moderate affinity at both the CB1 and CB2 receptors. It is a positional isomer of the more common drug JWH-250, though it is slightly less potent with a Ki of 17 nM at CB1, compared to 11 nM for JWH-250. Because of their identical molecular weight and similar fragmentation patterns, JWH-302 and JWH-250 can be very difficult to distinguish by GC-MS testing.

<span class="mw-page-title-main">MN-25</span> Chemical compound

MN-25 (UR-12) is a drug invented by Bristol-Myers Squibb, that acts as a reasonably selective agonist of peripheral cannabinoid receptors. It has moderate affinity for CB2 receptors with a Ki of 11 nM, but 22x lower affinity for the psychoactive CB1 receptors with a Ki of 245 nM. The indole 2-methyl derivative has the ratio of affinities reversed however, with a Ki of 8 nM at CB1 and 29 nM at CB2, which contrasts with the usual trend of 2-methyl derivatives having increased selectivity for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs JWH-098).

<span class="mw-page-title-main">O-1269</span> Chemical compound

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<span class="mw-page-title-main">LBP-1 (drug)</span> Chemical compound

LBP-1 is a drug originally developed by Organon for the treatment of neuropathic pain, It acts as a potent and selective cannabinoid receptor agonist, with high potency at both the CB1 and CB2 receptors, but low penetration of the blood–brain barrier. This makes LBP-1 peripherally selective, and while it was effective in animal models of neuropathic pain and allodynia, it did not produce cannabinoid-appropriate responding suggestive of central effects, at any dose tested.

<span class="mw-page-title-main">KM-233</span> Chemical compound

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<span class="mw-page-title-main">JWH-120</span> Chemical compound

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<span class="mw-page-title-main">JWH-149</span> Chemical compound

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<span class="mw-page-title-main">PTI-2</span> Chemical compound

PTI-2 (SGT-49) is an indole-based synthetic cannabinoid. It is one of few synthetic cannabinoids containing a thiazole group and is closely related to PTI-1. These compounds may be viewed as simplified analogues of indole-3-heterocycle compounds originally developed by Organon and subsequently further researched by Merck.

<span class="mw-page-title-main">PTI-1</span> Chemical compound

PTI-1 (SGT-48) is an indole-based synthetic cannabinoid. It is one of few synthetic cannabinoids containing a thiazole group and is closely related to PTI-2. These compounds may be viewed as simplified analogues of indole-3-heterocycle compounds originally developed by Organon and subsequently further researched by Merck.

<span class="mw-page-title-main">ADB-FUBHQUCA</span> Chemical compound

ADB-FUBHQUCA is a synthetic cannabinoid receptor agonist that has been sold as a designer drug, first reported in 2022. It is related to the previously reported compound ADB-FUBICA but with the central indole ring system expanded to a 1,4-dihydroquinoline structure. This breaks the aromaticity of the ring system, and ADB-FUBHQUCA is relatively low in potency compared to related compounds where the aromatic core is retained.

References

  1. Adam, J. M.; et al. (2010). "Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists". MedChemComm . 1. Royal Society of Chemistry: 54. doi:10.1039/c0md00022a.
  2. Kiyoi T, York M, Francis S, Edwards D, Walker G, Houghton AK, Cottney JE, Baker J, Adam JM (August 2010). "Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists". Bioorganic & Medicinal Chemistry Letters. 20 (16): 4918–21. doi:10.1016/j.bmcl.2010.06.067. PMID   20634067.
  3. Moir EM, Yoshiizumi K, Cairns J, Cowley P, Ferguson M, Jeremiah F, Kiyoi T, Morphy R, Tierney J, Wishart G, York M, Baker J, Cottney JE, Houghton AK, McPhail P, Osprey A, Walker G, Adam JM (December 2010). "Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists". Bioorganic & Medicinal Chemistry Letters. 20 (24): 7327–30. doi:10.1016/j.bmcl.2010.10.061. PMID   21074434.