Makara JK, Mor M, Fegley D, Szabo SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D. inhibition towards MGL. Subsequently, compound 21 was tested for its analgesic and anti-inflammatory activity using models previously explained.24 The acetic acid writhing test was used to assess analgesic activity in rats. Acetylsalicylate was used as a reference drug and was administered ip. As shown in Physique 3, 21 exhibited analgesic activity at a dose of 3.6 mg/kg 6b-Hydroxy-21-desacetyl Deflazacort (ip). A more potent effect was observed at a 10-fold higher dose indicating a dose-dependent effect. Furthermore, its enantiomer 22 exhibited comparable analgesic activity at the high dose of 36 mg/kg, but experienced weaker analgesic potency at the lower dose of 3.6 mg/kg. Open in a separate window Physique 3 In vivo analgesic activity of inhibitors 21 and 22. Control (), 22 (3.6 mg/kg, ), 21 (3.6 mg/kg, ?), 22 (36 mg/kg, ), 21 (36 mg/kg, ), aspirin (200 mg/kg, +). The rat paw carrageenan-induced edema assay was employed as a model for acute inflammation. Compound 21 exhibited in vivo anti-inflammatory activity (ED50 0.01 mmol/kg) comparable to that of the reference drug indomethacin (47% inhibition of inflammation at 0.01 mmol/kg administered ip). In conclusion, we synthesized a variety of long chain 1,2-diamines and related compounds and analyzed their effects around the endocannabinoid deactivating enzymes FAAH and MGL. We exhibited that (221.8 M) with in vivo analgesic and anti-inflammatory properties. Thus, synthetic selective inhibitors of MGL are potential candidates for the development of novel analgesic brokers. Acknowledgments The project was co-funded by the European Social Fund and National Resources-(EPEAEK II) PYTHAGORAS; Fund for International Collaborations, Northeastern University or college; and from your National Institutes on Drug Abuse (DA3801). The authors are grateful to Ying Pei and Nikolai M. Zvonok for the biochemical assays. References and notes 1. Kokotos G. Endocannabinoids. In: Kokotos G, Nicolaou A, editors. Bioactive Lipids. The Oily Press; Bridgewater, 6b-Hydroxy-21-desacetyl Deflazacort England: 2004. p. 245. [Google Scholar] 2. Lambert DM, Fowler CJ. J. Med. Chem. 2005;48:5059. [PubMed] [Google Scholar] 3. (a) Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminsky NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z. Biochem. Pharmacol. 1995;50:83. [PubMed] [Google Scholar](b) Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K. Biochem. Biophys. Res. Commun. 1995;215:89. [PubMed] [Google Scholar](c) Stella N, Schweitzer P, Piomelli D. Nature. 1997;388:773. [PubMed] [Google Scholar] 4. (a) Sugiura T, Kodaka T, Nakane S, Miyashita T, Kondo S, Suhara Y, Takayama H, Waku K, Seki C, Baba N, Ishima Y. J. Biol. Chem. 1999;274:2794. [PubMed] [Google Scholar](b) Gonsiorek W, Lunn C, Fan X, Narula S, Lyndell D, Hipkin RW. Mol. Pharmacol. 2000;57:1045. [PubMed] [Google Scholar] 5. (a) Piomelli D. Curr. Opin. Investig. Drugs. 2005;6:672. [PubMed] [Google Scholar](b) Di Marzo V, Bifulco M, De Petrocallis L. Nat. Rev. Drug Disc. 2004;3:771. [PubMed] [Google Scholar](c) Makriyannis A, Mechoulam R, Piomelli D. 2005. Neuropharmacology. 48:1068. [PubMed] [Google Scholar](d) Bahr BA, Karanian DA, Makanji SS, Makriyannis A. Expert Opin. Investig. Drugs. 2006;15:351. [PubMed] [Google Scholar] 6. (a) Desarnaud F, Cadas H, Piomelli D. J. Biol. Chem. 1995;270:6030. [PubMed] [Google Scholar](b) Ueda N, Kurahashi Y, Yamamoto S, Tokunaga T. J. Biol. Chem. 1995;270:23823. [PubMed] [Google Scholar](c) Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Nature. 1996;384:83. [PubMed] [Google Scholar](d) Goparaju SK, Ueda N, Yamaguchi H, Yamamoto S. FEBS Lett. 1998;422:69. [PubMed] [Google Scholar](e) Lang W, Qin C, Lin S, Khanolkar AD, Goutopoulos A, Fan P, Abouzid K, Meng Z, Biegel D, Makriyannis A. J. Med. Chem. 1999;42:896. [PubMed] [Google Scholar] 7. (a) Tornquist H, Belfrage P. J. Biol. Chem. 1976;251:813. [PubMed] [Google Scholar](b) Karlsson.Med. 2-amino oleic (29) acid does not inhibit MGL, but weakly inhibits 6b-Hydroxy-21-desacetyl Deflazacort FAAH. Thus, it appears that replacement of the CH2NH2 moiety of compound 21 by the CONH2 led to a compound without inhibition towards MGL. Subsequently, compound 21 was tested for its analgesic and anti-inflammatory activity using models previously explained.24 The acetic acid writhing test was used to assess analgesic activity in rats. Acetylsalicylate was used as a reference drug and was administered ip. As shown in Physique 3, 21 exhibited analgesic activity at a dose of 3.6 mg/kg (ip). A more potent effect was observed at a 10-fold higher dose indicating a dose-dependent effect. Furthermore, its enantiomer 22 exhibited comparable analgesic activity at the high dose of 36 mg/kg, but experienced weaker analgesic potency at the lower dose of 3.6 mg/kg. Open in a separate window Physique 3 In vivo analgesic activity of inhibitors 21 and 22. Control (), 22 (3.6 mg/kg, ), 21 (3.6 mg/kg, ?), 22 (36 mg/kg, ), 21 (36 mg/kg, ), aspirin (200 mg/kg, +). The rat paw carrageenan-induced edema assay was employed as a model for acute inflammation. Compound 21 exhibited in vivo anti-inflammatory activity (ED50 0.01 mmol/kg) comparable to that of the reference drug indomethacin (47% inhibition of inflammation at 0.01 mmol/kg administered ip). In conclusion, we synthesized a variety of long chain 1,2-diamines and related compounds and analyzed their effects around the endocannabinoid deactivating enzymes FAAH and MGL. We exhibited that (221.8 M) with in vivo analgesic and anti-inflammatory properties. Thus, synthetic selective inhibitors of MGL are potential candidates for the development of novel analgesic brokers. Acknowledgments The project was co-funded by the European Social Fund and National Resources-(EPEAEK II) PYTHAGORAS; Fund for International Collaborations, Northeastern University or college; and from your National Institutes on Drug Abuse (DA3801). The authors are grateful to Ying Pei and Nikolai M. Zvonok for the biochemical assays. Recommendations and notes 1. Kokotos G. Endocannabinoids. In: Kokotos G, Nicolaou A, editors. Bioactive Lipids. The Oily Press; Bridgewater, England: 2004. p. 245. [Google Scholar] 2. Lambert DM, Fowler CJ. J. Med. Chem. 2005;48:5059. [PubMed] [Google Scholar] 3. (a) Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminsky NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z. Biochem. Pharmacol. 1995;50:83. [PubMed] [Google Scholar](b) Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K. Biochem. Biophys. Res. Commun. 1995;215:89. [PubMed] [Google Scholar](c) Stella N, Schweitzer P, Piomelli D. Nature. 1997;388:773. [PubMed] [Google Scholar] 4. (a) Sugiura T, Kodaka T, 6b-Hydroxy-21-desacetyl Deflazacort Nakane S, Miyashita T, Kondo S, Suhara Y, Takayama H, Waku K, Seki C, Baba N, Ishima Y. J. Biol. Chem. 1999;274:2794. [PubMed] [Google Scholar](b) Gonsiorek W, Lunn C, Fan X, Narula S, Lyndell D, Hipkin RW. Mol. Pharmacol. 2000;57:1045. [PubMed] [Google Scholar] 5. (a) Piomelli D. Curr. Opin. Investig. Drugs. 2005;6:672. [PubMed] [Google Scholar](b) Di Marzo V, Bifulco M, De Petrocallis L. Nat. Rev. Drug Disc. 2004;3:771. [PubMed] [Google Scholar](c) Makriyannis A, Mechoulam R, Piomelli D. 2005. Neuropharmacology. 48:1068. [PubMed] [Google Scholar](d) Bahr BA, Karanian DA, Makanji SS, Makriyannis A. Expert Opin. Mouse monoclonal to CD4.CD4, also known as T4, is a 55 kD single chain transmembrane glycoprotein and belongs to immunoglobulin superfamily. CD4 is found on most thymocytes, a subset of T cells and at low level on monocytes/macrophages Investig. Drugs. 2006;15:351. [PubMed] [Google Scholar] 6. (a) Desarnaud F, Cadas H, Piomelli D. J. Biol. Chem. 1995;270:6030. [PubMed] [Google Scholar](b) Ueda N, Kurahashi Y, Yamamoto S, Tokunaga T. J. Biol. Chem. 1995;270:23823. [PubMed] [Google Scholar](c) Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Nature. 1996;384:83. [PubMed] [Google Scholar](d) Goparaju SK, Ueda N, Yamaguchi H, Yamamoto S. FEBS Lett. 1998;422:69. [PubMed] [Google Scholar](e) Lang W, Qin C, Lin S, Khanolkar AD, Goutopoulos A, Fan P, Abouzid K, Meng Z, Biegel D, Makriyannis A. J. Med. Chem. 1999;42:896. [PubMed].