Published: June 13, 2011 Copyright r 2011 American Chemical Society and American Society of Pharmacognosy 1636 dx.doi.org/10.1021/np200147c | J. Nat. Prod. 2011, 74, 1636–1639 NOTE pubs.acs.org/jnp Benzyl Derivatives with in Vitro Binding Affinity for Human Opioid and Cannabinoid Receptors from the Fungus Eurotium repens Jiangtao Gao, † Francisco Le on, † Mohamed M. Radwan, ‡,§ Olivia R. Dale, † Afeef S. Husni, † Susan P. Manly, ‡ Shari Lupien, ^ Xiaoning Wang, † Robert A. Hill, || Frank M. Dugan, ^ Horace G. Cutler, Δ and Stephen J. Cutler* , †, ‡ † Department of Medicinal Chemistry, ‡ National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, United States § Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt ^ USDA-ARS Western Regional Plant Introduction Station, Washington State University, Pullman, Washington 99164, United States ) National Centre for Advanced Bio-Protection Technologies, Lincoln University, Lincoln 7647, New Zealand Δ Natural Products Discovery Group, College of Pharmacy and Health Sciences, Mercer University, Atlanta, Georgia, 30341 b S Supporting Information ABSTRACT: Bioassay-guided fractionation of the fungus Eurotium repens resulted in the isolation of two new benzyl derivatives, (E)-2-(hept-1- enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)benzene-1,4-diol (1) and (E)-4-(hept-1-enyl)-7-(3-methylbut-2-enyl)-2,3-dihy- drobenzofuran-2,5-diol (2), along with seven known compounds (39) including five benzaldehyde compounds, flavoglaucin (3), tetrahydroauroglaucin (4), dihydroauroglaucin (5), auroglaucin (6), and 2-(2 0 ,3-epoxy-1 0 ,3 0 - heptadienyl)-6-hydroxy-5-(3-methyl- 2-butenyl)benzaldehyde (7), one diketopiperazine alkaloid, echinulin (8), and 5,7-dihydroxy-4-methylphthalide (9). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data. Compounds 14 and 6 showed good binding affinity for human opioid or cannabinoid receptors. These findings have important implications for psychoactive studies with this class of compounds. C entral nervous system (CNS) disorders are common world- wide problems, and annually about one-fourth of adult Americans suffer from a diagnosable psychotic disorder. 1 Neuro- pathic pain is defined as a type of pain that is caused by a lesion or dysfunction of the nervous system. Worldwide as much as 7% to 8% of the population is affected by neuropathic pain, while in the United States more than two million people suffer from this. 2 The treatment of neuropathic pain is challenging because the common causes are complex and may include diabetic neuro- pathy, nerve compression syndromes, postherpetic or trigeminal neuralgia, stroke, shingles, multiple sclerosis, spinal cord injury, cancer, and/or HIV infection. 3 The opioid and cannabinoid receptors are G-protein coupled receptors that have been classified into subtypes. The opioid receptor system includes three subtypes, δ, k, and μ, and the cannabinoid receptor system comprises at least two major subtypes, CB1 and CB2. 4,5 Studies show that ligands of opioid or cannabinoid receptors have long been known to modulate pain. 6 Furthermore, scientists found that components of neuropathic pain are affected significantly by the administration of opiates such as morphine and exogenous cannabinoids such as Δ 9 -tetrahydrocannabinol (compounds that have analgesic and addictive properties). 7 These observations suggest that the opioid and the cannabinoid receptor systems are altered during neuropathic pain. Opioid and cannabinoid recep- tor agonists are potent analgesics and remain promising treat- ments for patients with neuropathic pains. 8 Opioid and cannabinoid receptors are distributed in the regions associated with pain modulation. Agonists of opioid and cannabinoid receptors have been shown to activate pain inhibitory pathways in the central nervous system. 6 So far, the majority of clinically available opioid analgesics are μ-agonists and include morphine and its derivatives. 7 However, morphine and its derivatives have many side effects such as tolerance and dependency. 8 In order to meet the need for an efficacious analgesic without side effects, attention has focused on other opioid and cannabinoid receptors. Currently there are only a few agents that target k and CB2 receptors and none that target δ and Received: August 19, 2010