MN-25 explained

MN-25 (UR-12) is a drug invented by Bristol-Myers Squibb,[1] that acts as a reasonably selective agonist of peripheral cannabinoid receptors.[2] 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,[3] [4] 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).[5] [6]

Chemically, it is closely related to another indole-3-carboxamide synthetic cannabinoid, Org 28611, but with a different cycloalkyl substitution on the carboxamide, and the cyclohexylmethyl group replaced by morpholinylethyl, as in JWH-200 or A-796,260. Early compounds such as these have subsequently led to the development of many related indole-3-carboxamide cannabinoid ligands.[7] [8] [9] [10]

See also

Further reading

  1. Hynes J, Leftheris K, Wu H, Pandit C, Chen P, Norris DJ, Chen BC, Zhao R, Kiener PA, Chen X, Turk LA, Patil-Koota V, Gillooly KM, Shuster DJ, McIntyre KW . 6 . C-3 Amido-indole cannabinoid receptor modulators . Bioorganic & Medicinal Chemistry Letters . 12 . 17 . 2399–402 . September 2002 . 12161142 . 10.1016/s0960-894x(02)00466-3.
  2. Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD . 6 . Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity . Journal of Medicinal Chemistry . 53 . 1 . 295–315 . January 2010 . 19921781 . 10.1021/jm901214q .
  3. Chin CL, Tovcimak AE, Hradil VP, Seifert TR, Hollingsworth PR, Chandran P, Zhu CZ, Gauvin D, Pai M, Wetter J, Hsieh GC, Honore P, Frost JM, Dart MJ, Meyer MD, Yao BB, Cox BF, Fox GB . 6 . Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI . British Journal of Pharmacology . 153 . 2 . 367–79 . January 2008 . 17965748 . 2219521 . 10.1038/sj.bjp.0707506 .

Notes and References

  1. WO . 0158869 . application . Cannabinoid Receptor Modulators, Their Processes of Preparation, and use of Cannabinoid Receptor Modulators for Treating Respiratory and Non-Respiratory Diseases . 16 August 2001 . 8 February 2001 . 11 February 2000 . Leftheris K, Zhao R, Chen BC, Kiener P, Wu H, Pandit CR, Wrobleski S, Chen P, Hynes J, Longphre M, Norris DJ, Spergel S, Tokarski J . Bristol-Myers Squibb .
  2. Zhao R, Wang B, Wu H, Hynes J, Leftheris K, Balasubramanian B, Barrish JC, Chen BC . Improved procedure for the preparation of 7-methoxy-2-methyl-1-(2-morpholinoethyl)-1H-indole-3-carboxylic acid, key intermediate in the synthesis of novel 3-amidoindole and indolopyridone cannabinoid ligands . Arkivoc . 20 December 2009 . 2010 . 6 . 89–95 . 10.3998/ark.5550190.0011.610 . free . 2027/spo.5550190.0011.610 . free .
  3. Hynes J, Leftheris K, Wu H, Pandit C, Chen P, Norris DJ, Chen BC, Zhao R, Kiener PA, Chen X, Turk LA, Patil-Koota V, Gillooly KM, Shuster DJ, McIntyre KW . 6 . C-3 Amido-indole cannabinoid receptor modulators . Bioorganic & Medicinal Chemistry Letters . 12 . 17 . 2399–402 . September 2002 . 12161142 . 10.1016/S0960-894X(02)00466-3 .
  4. Wrobleski ST, Chen P, Hynes J, Lin S, Norris DJ, Pandit CR, Spergel S, Wu H, Tokarski JS, Chen X, Gillooly KM, Kiener PA, McIntyre KW, Patil-Koota V, Shuster DJ, Turk LA, Yang G, Leftheris K . Rational design and synthesis of an orally active indolopyridone as a novel conformationally constrained cannabinoid ligand possessing antiinflammatory properties . Journal of Medicinal Chemistry . 46 . 11 . 2110–6 . May 2003 . 12747783 . 10.1021/jm020329q .
  5. Huffman JW, Padgett LW . Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes . Current Medicinal Chemistry . 12 . 12 . 1395–411 . 2005 . 15974991 . 10.2174/0929867054020864 .
  6. Manera C, Tuccinardi T, Martinelli A . Indoles and related compounds as cannabinoid ligands . Mini Reviews in Medicinal Chemistry . 8 . 4 . 370–87 . April 2008 . 18473928 . 10.2174/138955708783955935 .
  7. Adam JM, Cairns J, Caulfield W, Cowley P, Cumming I, Easson M, etal . Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists . 10.1039/c0md00022a . MedChemComm. Royal Society of Chemistry. 1 . 54–60 . 2010 .
  8. Kiyoi T, York M, Francis S, Edwards D, Walker G, Houghton AK, Cottney JE, Baker J, Adam JM . 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 . August 2010 . 20634067 . 10.1016/j.bmcl.2010.06.067 .
  9. 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 . 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 . December 2010 . 21074434 . 10.1016/j.bmcl.2010.10.061 .
  10. Blaazer AR, Lange JH, van der Neut MA, Mulder A, den Boon FS, Werkman TR, Kruse CG, Wadman WJ . Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: design, synthesis, structure-activity relationships, physicochemical properties and biological activity . European Journal of Medicinal Chemistry . 46 . 10 . 5086–98 . October 2011 . 21885167 . 10.1016/j.ejmech.2011.08.021 .

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