Isolation and Chemical Modification of Clerodane Diterpenoids from Salvia Species as Potential Agonists at the ϰ‐Opioid Receptor.

Abstract

The clerodane diterpenoid salvinorin A (1), the main active component of the psychotropic herb Salvia divinorum, has been reported to be a potent agonist at the k-opioid receptor. Computer modeling suggested that splendidin (2) from S. splendens, as well as related compounds, might possess similar activities. In the present study, this hypothesis was tested by determination of the binding properties of a series of structural congeners, compounds 2 -8, at the m-, d-, and k-opioid receptors. However, none of these compounds showed significant binding to any of the opioid-receptor subtypes, thus disproving the above hypothesis.The novel compounds 7 and 8 were obtained semi-synthetically by selective modification of salvifarin (5), isolated from Salvia farinacea, upon epoxide-ring opening with AcOH in the presence of indium(III) triflate. Also, the X-ray crystal structure of salvifaricin (6; Fig.), obtained from S. farinacea, was determined for the first time and used, in combination with in-depth NMR experiments, to elucidate the absolute configurations of the new products. Our experiments demonstrate that the relatively wellaccessible diterpenoid 6 could be used as starting material for future studies into the structure -activity relationship at the k-opioid receptor.Introduction. -Salvia divinorum, also referred to as magic mint or holy mint, is a psychotropic plant first described in the 1960s [1]. A number of clerodane diterpenoids have been isolated from this species [2], of which salvinorin A (1) was identified as the major active constituent [3] [4]. This compound was subsequently shown to act as an agonist at the k-opioid receptor, the first non-nitrogenous compound to do so [5] [6]. Modeling studies with 1 led to the hypothesis that splendidin (2), another clerodane diterpenoid from Salvia splendens, might also possess k-opioid activity [5]. However, the study of structure -activity relationships (SAR) by a number of groups using modified derivatives of 1 have shown particular structural requirements lacking in 2, including an acetyl (Ac) group or another small substituent at the C(2) atom [7], as well as trans-fused B/C rings, with a b-orientated H-atom at C(8) [8].The purpose of the present study was to test whether or not splendidin (2) is, indeed, a k-opioid agonist, and to compare its biological properties with those of other diterpenoids from S. splendens, including salviarin (3) and splenolide B (4). We also isolated the clerodanes salvifarin (5) and salvifaricin (6) from S. farinacea, and tested them together with the semi-synthetic derivatives 7 and 8.

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…and Schult. also identified several neoclerodanes that are structurally similar to those found in S. divinorum (Fontana et al, 2006), although these and most semisynthetic analogs (Li et al, 2007;Fontana et al, 2008Fontana et al, , 2009 proved to be largely inactive at KOP receptors (see section IV.A).…”

“…Constituents of S. splendens contain a trans-decalin ring system similar to that of salvinorin A; however, they differ significantly in that they are epimeric at both C-8 and C-12. Thorough synthetic modification of salvisplendens A to D failed to produce ligands with significant KOP, MOP, or DOP affinity, however, highlighting the structural requirements for KOP receptor binding that are contained in salvinorin A-based ligands (Li et al, 2007;Fontana et al, 2008).…”

The spiritual sense, prayer and traditional American Indian healing

“…Tobacco, such as Nicotiana attenuata, has been used by Cahuilla and other American Indians for spiritual experiences and for rites of passage (Garcia et al, 2009). Salvia divinorum, that contains salvinorin A, is the way to God for Mazatec people who use the plant for sacred dreams (Li et al, 2007). Morning glory seeds from Ipomoea tricolor and I. corymbosa contain the ergot alkaloids, ergonovine and ergine, and are used for sacred dreams (Hofman, 1971).…”

“…Nicotinic kinins may interact with NAChR also. Salvinorin A from Salvia divinorum interacts with kappa opioid receptors (KOR) (Li et al, 2007). Endorphins and enkephalins, from kinetic activities, interact with mu opioid receptors (MOR) in the brain (Marek et al, 1998).…”

“…Mescaline can cause fatality through vomiting and aspiration (Nolte et al, 1999). Salvinorin A is a KOR and dopamine receptor type 2 (D2) agonist (Li et al, 2007;Seeman et al, 2009). KOR agonists, such as enadoline, can induce locomotor impairment and psychotomimetic effects that could be life threatening (Walsh et al, 2001).…”