Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum:  Semisynthesis of Salvinicins A and B and Other Chemical Transformations of Salvinorin A

Abstract

Salvinorin A (1) is a hallucinogenic neoclerodane diterpene isolated from the widely available psychoactive plant Salvia divinorum and is the first example of a non-nitrogenous opioid receptor ligand. At present, there is little information available as to why this compound is selective for κ opioid receptors. One approach to better understanding the mode of binding of 1 at κ receptors is to systematically alter the structure of 1 and examine the effects on opioid receptor affinity and activity. Currently, there is a paucity of methods described for the preparation of analogues derived from 1. Here, we report the investigation of several chemical transformations of 1 isolated from S. divinorum. In particular, this work provides a semisynthesis of salvinicins A (2) and B (3) and has identified 10a as the first neoclerodane diterpene with δ opioid antagonist activity. Keywords salvinorin A; salvinicin A; salvinicin B; neoclerodane diterpenes; and Salvia divinorumExtracts of the opium poppy, Papaver somniferum, have been used for centuries to relieve pain and to induce sleep. 1 Among the most important constituents in opium are the alkaloids morphine and codeine. Many of the agonists and antagonists derived from these alkaloids are essential for the practice of modern medicine. While many potent agonists are effective analgesics, they have undesirable side effects, such as tolerance, dependence, and respiratory depression. 2Recently, opioid receptors have been implicated in the actions of salvinorin A (1), the major active ingredient of Salvia divinorum Epling & Játiva (Lamiaceae), a hallucinogenic plant that has been used historically in the traditional practices of the Mazatecs in Oaxaca, This finding is unique because 1 represents the only known lipid-like small molecule that † This work was presented in part at the American Society of Pharmacognosy 46 th Annual Meeting, July 23 -July 27, 2005.*To whom correspondence should be addressed, S327 PHAR, MNPC, 115 S. Grand Ave. Iowa City, Iowa 52242-1112, Telephone: (319) Fax: (319) selectively and potently activates a peptidergic G-protein coupled receptor (GPCR). 7, 8 Diterpene 1 was found to be a high efficacy agonist for κ opioid receptors (κOR). 6, 9 Thus, 1 provides a truly unique template for the development of novel agents to attenuate pain with a potential for reduced abuse liability.Recently, we 10, 11 and others 12-15 have described the isolation and synthesis of several novel neoclerodane diterpenes with opioid receptor activity. Among these compounds were salvinicin A (2) and salvinicin B (3). 11 Diterpene 2 was identified as a partial κOR agonist, whereas, 3 was found to be the first neoclerodane diterpene with μ antagonist activity. There is a growing body of information as to why 1 and related analogues have activity at opioid receptors. 10, 11, 13-17 However, there are few synthetic methods described for related analogues of 1. Based on previous reports, 10, 11, 13,14 the C-2 position and furan ring appear to be important sites for the op...

Effects of Salvinorin A, a κ-Opioid Hallucinogen, on a Neuroendocrine Biomarker Assay in Nonhuman Primates with High κ-Receptor Homology to Humans

“…Salvinorin A was extracted from commercially obtained S. divinorum leaves (Ethnogens.com, Berkeley, CA) in the laboratory of Dr. T.E. Prisinzano, as described previously (Tidgewell Harding et al, 2006). In brief, dried S. divinorum leaves (1.5 kg) were ground to a fine powder and percolated with acetone.…”

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…6) Harding et al, 2006b). Inversion of the C-2 acetate of salvinorin A (111) resulted in a significant loss of affinity at KOP receptors and was found to be the first neoclerodane diterpene with DOP antagonist activity (Harding et al, 2006b).…”

“…6) Harding et al, 2006b). Inversion of the C-2 acetate of salvinorin A (111) resulted in a significant loss of affinity at KOP receptors and was found to be the first neoclerodane diterpene with DOP antagonist activity (Harding et al, 2006b). Epimerization of the C-2 position was detrimental for binding affinity and potency of C-2 esters (111-113), ethers (114-116), thiols (117, 118), and amides (119-124) Bikbulatov et al, 2007).…”

Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Selective modification of the furan ring

“…8,9 Several recent reports have begun to explore the structure-activity relationships of 2a at opioid receptors. 10,11,7,[12][13][14][15] As part of our program to develop novel analgesics with a potential for reduced tolerance and dependence, we initiated studies to prepare several heterocyclic replacements for the furan ring present in 2a. This was based on the activities of salvinicin A and B, as well as, our goal to reduce the potential for hepatotoxicity seen with furan containing natural products.…”