Herkinorin

Herkinorin
IUPAC ime
	(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(benzoiloksi)-2-(3-furanil)dodekahidro -6a,10b-dimetil-4,10-diokso-2H-nafto-[2,1-c]piran-7-karboksilno kiselinski metil estar
Pravni status
Pravni status	Legalan;
Identifikatori
ATC kod	none
PubChem	CID 11431898
ChemSpider	9606773
ChEMBL	CHEMBL363324
Hemijski podaci
Formula	C28H30O8
Molarna masa	494,55 g/mol
	SMILES O=C(OC)[C@H]3[C@@]4(CC[C@H]5C(=O)O[C@H](c1ccoc1)C[C@@]5([C@H]4C(=O)[C@@H](OC(=O)c2ccccc2)C3)C)C; ;
	InChI InChI=1S/C28H30O8/c1-27-11-9-18-26(32)36-21(17-10-12-34-15-17)14-28(18,2)23(27)22(29)20(13-19(27)25(31)33-3)35-24(30)16-7-5-4-6-8-16/h4-8,10,12,15,18-21,23H,9,11,13-14H2,1-3H3/t18-,19-,20-,21-,23-,27-,28-/m0/s1 ; Key:PYDQMXRFUVDCHC-XAGHGKQISA-N ;

Herkinorin je opioidni analgetik koji je analog prirodnog proizvoda Salvinorina A. On je otkriven 2005. tokom ispitivanja odnosa strukture i aktivnosti neoklerodan diterpena, familije hemijskih jedinjenja kojoj pripada Salvinorin A.^[1]

Za razliku od salvinorina A koji je selektivni κ-opioidni agonist bez znatnog afiniteta za μ-opioidni receptor, herkinorin je μ-opioidni agonist sa više nego 100x većim μ-opioidnim afinitetom i 50x nižim κ-opioidnim afinitetom u poređenju sa salvinorinom A.^[2]^[3] Herkinorin je semisintetičko jedinjenje, nastalo od salvinorina B, koji nastaje deacetilacijom salvinorina A. Dok su oba jedinjenja, salvinorin A i salvinorin B, nađena u biljci Salvia divinorum, salvinorin A je prisutan u većim količinama.^[4]

Ispitivanja na primatima su pokazala da on deluje kao periferno aktivni μ i κ agonist sa brzim početkom dejstva.^[5] Za razliku od većine μ-opioidnih agonista, herkinorin ne promoviše regrutovanje β-arestina-2 na intracelularni domen μ-opioidnog receptora, niti indukuje internalizaciju receptora.^[6] To znači da herkinorin možda ne proizvodi toleranciju i zavisnost za razliku od drugih opioida, mada je razvoj tolerancije putem drugih mehanizama bio zapažen,^[7] i neki drugi analozi srodni herkinorinu mogu da regrutuju β-arestine.^[8]

Vidi još

Reference

^ Harding, Wayne W.; Tidgewell, Kevin; Byrd, Nathan; Cobb, Howard; Dersch, Christina M.; Butelman, Eduardo R.; Rothman, Richard B.; Prisinzano, Thomas E. (2005). „Neoclerodane Diterpenes as a Novel Scaffold for μ Opioid Receptor Ligands”. Journal of Medicinal Chemistry. 48 (15): 4765—4771. PMID 16033256. doi:10.1021/jm048963m.
^ Tidgewell, Kevin; Harding, Wayne W.; Lozama, Anthony; Cobb, Howard; Shah, Kushal; Kannan, Pavitra; Dersch, Christina M.; Parrish, Damon; Deschamps, Jeffrey R.; Rothman, Richard B.; Prisinzano, Thomas E. (2006). „Synthesis of Salvinorin a Analogues as Opioid Receptor Probes”. Journal of Natural Products. 69 (6): 914—918. PMID 16792410. doi:10.1021/np060094b.
^ Holden, Kenneth G.; Tidgewell, Kevin; Marquam, Alfred; Rothman, Richard B.; Navarro, Hernán; Prisinzano, Thomas E. (2007). „Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Exploration of the 1-position”. Bioorganic & Medicinal Chemistry Letters. 17 (22): 6111—6115. PMC 2111044 . PMID 17904842. doi:10.1016/j.bmcl.2007.09.050.
^ Tidgewell, Kevin; Harding, Wayne W.; Schmidt, Mark; Holden, Kenneth G.; Murry, Daryl J.; e. Prisinzano, Thomas (2004). „A facile method for the preparation of deuterium labeled salvinorin A: Synthesis of [2,2,2-2H3]-salvinorin A”. Bioorganic & Medicinal Chemistry Letters. 14 (20): 5099—5102. PMID 15380207. doi:10.1016/j.bmcl.2004.07.081.
^ Butelman ER, Rus S, Simpson DS, Wolf A, Prisinzano TE, Kreek MJ (2008). „The effects of herkinorin, the first mu-selective ligand from a salvinorin A-derived scaffold, in a neuroendocrine biomarker assay in nonhuman primates”. The Journal of Pharmacology and Experimental Therapeutics. 327 (1): 154—60. PMC 2614932 . PMID 18593955. doi:10.1124/jpet.108.140079.
^ Groer, C. E.; Tidgewell, K.; Moyer, R. A.; Harding, W. W.; Rothman, R. B.; Prisinzano, T. E.; Bohn, L. M. (2007). „An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization”. Molecular Pharmacology. 71 (2): 549—557. PMC 3926195 . PMID 17090705. doi:10.1124/mol.106.028258.
^ Xu, H.; Partilla, J. S.; Wang, X.; Rutherford, J. M.; Tidgewell, K.; Prisinzano, T. E.; Bohn, L. M.; Rothman, R. B. (2007). „A comparison of noninternalizing (Herkinorin) and internalizing (DAMGO) mu-opioid agonists on cellular markers related to opioid tolerance and dependence”. Synapse (New York, N.Y.). 61 (3): 166—175. PMID 17152090. S2CID 23678472. doi:10.1002/syn.20356.
^ Tidgewell K, Groer CE, Harding WW, Lozama A, Schmidt M, Marquam A, Hiemstra J, Partilla JS, Dersch CM, Rothman RB, Bohn LM, Prisinzano TE (2008). „Herkinorin analogues with differential beta-arrestin-2 interactions”. Journal of Medicinal Chemistry. 51 (8): 2421—31. PMC 2494883 . PMID 18380425. doi:10.1021/jm701162g.

Spoljašnje veze

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[1] Harding, Wayne W.; Tidgewell, Kevin; Byrd, Nathan; Cobb, Howard; Dersch, Christina M.; Butelman, Eduardo R.; Rothman, Richard B.; Prisinzano, Thomas E. (2005). „Neoclerodane Diterpenes as a Novel Scaffold for μ Opioid Receptor Ligands”. Journal of Medicinal Chemistry. 48 (15): 4765—4771. PMID 16033256. doi:10.1021/jm048963m.

[2] Tidgewell, Kevin; Harding, Wayne W.; Lozama, Anthony; Cobb, Howard; Shah, Kushal; Kannan, Pavitra; Dersch, Christina M.; Parrish, Damon; Deschamps, Jeffrey R.; Rothman, Richard B.; Prisinzano, Thomas E. (2006). „Synthesis of Salvinorin a Analogues as Opioid Receptor Probes”. Journal of Natural Products. 69 (6): 914—918. PMID 16792410. doi:10.1021/np060094b.

[3] Holden, Kenneth G.; Tidgewell, Kevin; Marquam, Alfred; Rothman, Richard B.; Navarro, Hernán; Prisinzano, Thomas E. (2007). „Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Exploration of the 1-position”. Bioorganic & Medicinal Chemistry Letters. 17 (22): 6111—6115. PMC 2111044 . PMID 17904842. doi:10.1016/j.bmcl.2007.09.050.

[4] Tidgewell, Kevin; Harding, Wayne W.; Schmidt, Mark; Holden, Kenneth G.; Murry, Daryl J.; e. Prisinzano, Thomas (2004). „A facile method for the preparation of deuterium labeled salvinorin A: Synthesis of [2,2,2-2H3]-salvinorin A”. Bioorganic & Medicinal Chemistry Letters. 14 (20): 5099—5102. PMID 15380207. doi:10.1016/j.bmcl.2004.07.081.

[pmid18593955-5] Butelman ER, Rus S, Simpson DS, Wolf A, Prisinzano TE, Kreek MJ (2008). „The effects of herkinorin, the first mu-selective ligand from a salvinorin A-derived scaffold, in a neuroendocrine biomarker assay in nonhuman primates”. The Journal of Pharmacology and Experimental Therapeutics. 327 (1): 154—60. PMC 2614932 . PMID 18593955. doi:10.1124/jpet.108.140079.

[6] Groer, C. E.; Tidgewell, K.; Moyer, R. A.; Harding, W. W.; Rothman, R. B.; Prisinzano, T. E.; Bohn, L. M. (2007). „An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization”. Molecular Pharmacology. 71 (2): 549—557. PMC 3926195 . PMID 17090705. doi:10.1124/mol.106.028258.

[7] Xu, H.; Partilla, J. S.; Wang, X.; Rutherford, J. M.; Tidgewell, K.; Prisinzano, T. E.; Bohn, L. M.; Rothman, R. B. (2007). „A comparison of noninternalizing (Herkinorin) and internalizing (DAMGO) mu-opioid agonists on cellular markers related to opioid tolerance and dependence”. Synapse (New York, N.Y.). 61 (3): 166—175. PMID 17152090. S2CID 23678472. doi:10.1002/syn.20356.

[pmid18380425-8] Tidgewell K, Groer CE, Harding WW, Lozama A, Schmidt M, Marquam A, Hiemstra J, Partilla JS, Dersch CM, Rothman RB, Bohn LM, Prisinzano TE (2008). „Herkinorin analogues with differential beta-arrestin-2 interactions”. Journal of Medicinal Chemistry. 51 (8): 2421—31. PMC 2494883 . PMID 18380425. doi:10.1021/jm701162g.

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