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A number of herbal products have been used for treating various psychiatric disorders including anxiety, depression and addiction. Among these products, the extract of Cyperus rotundus has been used as a folk medicinal herb in Korea, China, India and Japan for the treatment of spasm and stomach disorders and the main ingredients of the extract are α-cyperone, β-selinene, cyperene, cyperol and nootkatene. Recent reports revealed that the extract of Cyperus rotundus possesses analgesic, nootropic, sedative, anti-inflammatory, antipyretic and antifungal activity. In addition, the neuroprotective effects of the herb were reported in Parkinson’s disease and cerebral ischemia model. As part of our program to develop new natural materials to treat various psychiatric disorders, we have investigated a number of herbal products to test their usefulness and therapeutic benefits for the treatment of depression, anxiety and drug dependence. We found that, among the various ingredients of Cyperus rotundus extract, α-cyperone (Figure 1.) has a binding affinity in vitro to cannabinoid-1 (CB1) and sigma-1 receptor (IC50 = 1.9 μM and 22.1 μM, respectively). Since sigma-1 and CB1 receptor binding affinity are closely related to the physiological effects from drug addiction, depression and anxiety in receptors throughout our body, we have synthesized various α-cyperone derivatives with the aim to improve both the selectivity of CB1 receptor binding affinity versus sigma-1 receptor binding affinity and the potency simultaneously. Here, we report the syntheses of some α-cyperone derivatives containing a heteroatom moiety at the C7 position and their selective binding affinities in vitro for the sigma-1 and CB1 receptors. We first synthesized α-cyperone 1 by following the previously reported synthetic routes. In brief, azeotropic imination of (+)-dihydrocarvone and (R)-(+)-1-phenylethylamine followed by alkylation with a slight excess of ethyl vinyl ketone (EVK) in THF at 40 C produced the Micheal adduct. The resulting adduct was hydrolyzed and then treated with sodium methoxide at room temperature to give an easily separable mixture of α-cyperone 1 and its side product. Flash chromatography resulted in pure α-cyperone 1 in a 30% yield from (+)-dihydrocarvone. The α-cyperone derivatives were synthesized as illustrated in Scheme 1. Reduction of α-cyperone with NaBH4 in ethanol produced the allylic alcohol 2. The 7-substituted α-cyperone derivatives were synthesized from nucleophilic substitution reaction of the chloride group in compound 3 with appropriate nucleophiles. Accordingly, after the allylic chloride derivative 3 was synthesized from compound 1 using hydroFigure 1. Structure of α-cyperone (1).

Syntheses of 7-Substituted α-Cyperone Derivatives for Selective Sigma-1 Receptor over Cannabinoid-1 Receptor Binding Affinities