Discovery of highly potent analgesic activity of isopulegol-derived (2R,4aR,7R,8aR)-4,7-dimethyl-2-(thiophen-2-yl)octahydro-2H-chromen-4-ol
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A large set of chiral heterocyclic compounds with the octahydro-2H-chromene scaffold was first obtained by a reaction of (−)-isopulegol and (+)-neoisopulegol with furan-2-carbaldehyde, thiophene-2-carbaldehyde and their derivatives and isomers in the presence of montmorillonite K10 clay. Most of the (−)-isopulegol-derived compounds exhibited a significant analgesic activity in the acetic acid-induced writhing test. Compound 3b obtained by a reaction of (−)-isopulegol with thiophene-2-carbaldehyde demonstrated a significant analgesic effect in this test within 15 min after oral administration at the dose of 1 mg/kg and retains the effect for at least 24 h. Compound 3b exhibited analgesic activity in the hot plate test also. A change in the sulfur atom position in the aromatic ring was found to lead to the effect reversal in the hot plate test.
KeywordsTerpene Chromene Isopulegol Analgesic activity Acetic acid-induced writhing test Hot plate test
Authors are grateful to the Russian Foundation for Basic Research (Grant No 13-03-00206a) for the financial support.
- Ardashov OV, Pavlova AV, Il’ina IV, Morozova EA, Korchagina DV, Karpova EV, Volcho KP, Tolstikova TG, Salakhutdinov NF (2011) Highly potent activity of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex3-ene-1,2-diol in animal models of Parkinson’s disease. J Med Chem 54:3866–3874CrossRefPubMedGoogle Scholar
- Bihel F, Humbert J-P, Schneider S, Bertin I, Wagner P, Schmitt M, Laboureyras E, Petit-Demoulière B, Schneider E, Mollereau C, Simonnet G, Simonin F, Bourguignon J-J (2015) Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia. ACS Chem Neurosci 6:438–445CrossRefPubMedGoogle Scholar
- Eddy NB, Leimbach D (1953) Synthetic analgesics. II. Dithienylbutenylamines and dithienylbutylamines. J Pharm Exp Ther 107:385–393Google Scholar
- EPA (2002) Health effects test guideline 870.1100: Acute oral toxicity, U.S. EPA document 712-C-02- 190. U.S. EPA, Office of Prevention, Pesticides and Toxic SubstancesGoogle Scholar
- Koster R, Anderson M, De Beer EJ (1959) Acetic acid for analgesic screening. Fed Proc 18:412–415Google Scholar
- Mikhalchenko OS, Volcho KP, Salakhutdinov NF (2013b) Synthesis of heterocyclic compounds by interaction of aldehydes with monoterpenoids. In: Torrioni L, Pescasseroli E (eds) New developments in aldehydes research. Nova Science Publishers, New York City, pp 49–80Google Scholar
- Nelson DW, Frost JM, Tietje KR, Florjancic AS, Ryther K, Carroll WA, Dart MJ, Daza AV, Hooker BA, Grayson GK, Fan Y, Garrison TR, El-Kouhen OF, Yao B, Pai M, Chandran P, Zhu C, Hsieh GC, Meyer MD (2012) Synthesis and evaluation of 2-amido-3-carboxamide thiophene CB2 receptor agonists for pain management. Bioorg Med Chem Lett 22:2604–2608CrossRefPubMedGoogle Scholar
- Pavlova A, Mikhalchenko O, Rogachev A, Il’ina I, Korchagina D, Gatilov Y, Tolstikova T, Volcho K, Salakhutdinov N (2015) Synthesis and analgesic activity of stereoisomers of 2-(3(4)-hydroxy-4(3)-methoxyphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols. Med Chem Res 24:3821–3830CrossRefGoogle Scholar
- Sarigol D, Uzgoren-Baran A, Tel BC, Somuncuoglu EI, Kazkayasi I, Ozadali-Sari K, Unsal-Tan O, Okay G, Ertan M, Tozkoparan B (2015) Novel thiazolo[3,2-b]-1,2,4-triazoles derived from naproxen with analgesic/anti-inflammatory properties: synthesis, biological evaluation and molecular modeling studies. Bioorg Med Chem 23:2518–2528CrossRefPubMedGoogle Scholar
- Thur Y, Bhalerao A, Munshi Z, Pansare N, Mann K, Hanauer G, Kley H-P, Nappe S, Weiss-Haljiti C, Ostermann C, Zitt C, Schaefer M, Mondal D, Siddiki AA, Armugam V, Gudaghe V, Gupta M, Rayudu P, Dautzenberg FM, Das Sarma K (2012) Structure–activity relationships of 2-arylamido-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide derivatives as cannabinoid receptor agonists and their analgesic action. Bioorg Med Chem Lett 22:7314–7321CrossRefPubMedGoogle Scholar
- Timofeeva MN, Volcho KP, Mikhalchenko OS, Panchenko VN, Krupskaya VV, Tsybulya SV, Gil A, Vicente MA, Salakhutdinov NF (2015) Synthesis of octahydro-2H-chromen-4-ol from vanillin and isopulegol over acid modified montmorillonite clays: effect of acidity on the Prins cyclization. J Mol Catal A Chem 398:26–34CrossRefGoogle Scholar