Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Nat Chem. 2024 Nov;16(11):1735-1736. doi: 10.1038/s41557-024-01659-x.

The original caretakers of salvinorin A and recognizing Indigenous contributions 
to science.

Clay KJ(1)(2)(3), Shenvi RA(4)(5)(6).

Author information:
(1)Department of Chemistry, Scripps Research, La Jolla, CA, USA. 
khalydc@scripps.edu.
(2)Department of Molecular and Cell Biology, Scripps Research, La Jolla, CA, 
USA. khalydc@scripps.edu.
(3)Graduate School of Chemical and Biological Sciences, Scripps Research, La 
Jolla, CA, USA. khalydc@scripps.edu.
(4)Department of Chemistry, Scripps Research, La Jolla, CA, USA. 
rshenvi@scripps.edu.
(5)Department of Molecular and Cell Biology, Scripps Research, La Jolla, CA, 
USA. rshenvi@scripps.edu.
(6)Graduate School of Chemical and Biological Sciences, Scripps Research, La 
Jolla, CA, USA. rshenvi@scripps.edu.

DOI: 10.1038/s41557-024-01659-x
PMID: 39438762


2. Physiol Plant. 2024 Sep-Oct;176(5):e14569. doi: 10.1111/ppl.14569.

Identification of clerodane diterpene modifying cytochrome P450 (CYP728D26) in 
Salvia divinorum - en route to psychotropic salvinorin A biosynthesis.

Ngo I(1), Kumar R(1), Li L(2), Kim SW(3), Kwon M(1)(3), Ro DK(1).

Author information:
(1)Department of Biological Sciences, University of Calgary, 2500 University Dr. 
NW, Calgary, Alberta, Canada.
(2)The Metabolomics Innovation Centre and Department of Chemistry, University of 
Alberta, Edmonton, Alberta, Canada.
(3)Division of Applied Life Science (BK21 Four), ABC-RLRC, RIMA, Gyeongsang 
National University, Jinju, Republic of Korea.

Salvia divinorum is a hallucinogenic plant native to the Oaxaca in Mexico. The 
active ingredient for psychotropic effects in this plant is salvinorin A, a 
potent and highly selective κ-opioid receptor agonist. Salvinorin A is distinct 
from other well-known opioids, such as morphine and codeine, in that it is a 
non-nitrogenous diterpenoid with no affinity for μ-opioid receptor, the prime 
receptor of alkaloidal opioids. A terpene opioid that selectively targets a new 
opioid receptor (κ-opioid receptor) can be instrumental in developing 
alternative analgesics. Elucidation of the salvinorin A biosynthetic pathway can 
help bio-manufacture diverse semi-synthetic derivatives of salvinorin A but, to 
date, only two enzymes in the Salvinorin A pathway have been identified. Here, 
we identify CYP728D26 that catalyzes a C18 oxygenation on crotonolide G, which 
bears a clerodane backbone. Biochemical identity of CYP728D26 was validated by 
in vivo reconstitution in yeast, 1H- and 13C-NMR analyses of the purified 
product, and kinetic analysis of CYP728D26 with a Km value of 13.9 μM. Beyond 
the single oxygenation on C18, collision-induced dissociation analysis suggested 
two additional oxygenations are catalyzed by CYP728D26 to form crotonoldie G 
acid, although this carboxylic acid form is a minor product. Its close homologue 
CYP728D25 exhibited a C1-hydroxylation on the clerodane backbone in a 
reconstituted yeast system. However, CYP728D25 showed no activity in in vitro 
assays. This result implies that catalytic activities observed from 
overexpression systems should be interpreted cautiously. This work identified a 
new CYP catalyst and advanced our knowledge of salvinorin A biosynthesis.

© 2024 The Author(s). Physiologia Plantarum published by John Wiley & Sons Ltd 
on behalf of Scandinavian Plant Physiology Society.

DOI: 10.1111/ppl.14569
PMID: 39377159 [Indexed for MEDLINE]


3. BMC Plant Biol. 2024 Oct 1;24(1):914. doi: 10.1186/s12870-024-05633-0.

A chromosome level reference genome of Diviner's sage (Salvia divinorum) 
provides insight into salvinorin A biosynthesis.

Ford SA(1), Ness RW(2)(3)(4), Kwon M(5)(6), Ro DK(5), Phillips MA(7)(8).

Author information:
(1)Department of Cell and Systems Biology, University of Toronto, Toronto, ON, 
M5S 3G5, Canada.
(2)Department of Cell and Systems Biology, University of Toronto, Toronto, ON, 
M5S 3G5, Canada. rob.ness@utoronto.ca.
(3)Department of Biology, University of Toronto - Mississauga, Mississauga, ON, 
L5L 1C6, Canada. rob.ness@utoronto.ca.
(4)Department of Ecology and Evolutionary Biology, University of Toronto, 
Toronto, ON, M5S 3G5, Canada. rob.ness@utoronto.ca.
(5)Department of Biological Sciences, University of Calgary, Calgary, AB, T2N 
1N4, Canada.
(6)Present Address: Division of Applied Life Science (BK21 Four), ABC-RLRC, 
RIMA, Gyeongsang National University, Jinju, 52828, Republic of Korea.
(7)Department of Cell and Systems Biology, University of Toronto, Toronto, ON, 
M5S 3G5, Canada. michaelandrew.phillips@utoronto.ca.
(8)Department of Biology, University of Toronto - Mississauga, Mississauga, ON, 
L5L 1C6, Canada. michaelandrew.phillips@utoronto.ca.

BACKGROUND: Diviner's sage (Salvia divinorum; Lamiaceae) is the source of the 
powerful hallucinogen salvinorin A (SalA). This neoclerodane diterpenoid is an 
agonist of the human Κ-opioid receptor with potential medical applications in 
the treatment of chronic pain, addiction, and post-traumatic stress disorder. 
Only two steps of the approximately twelve step biosynthetic sequence leading to 
SalA have been resolved to date.
RESULTS: To facilitate pathway elucidation in this ethnomedicinal plant species, 
here we report a chromosome level genome assembly. A high-quality genome 
sequence was assembled with an N50 value of 41.4 Mb and a BUSCO completeness 
score of 98.4%. The diploid (2n = 22) genome of ~ 541 Mb is comparable in size 
and ploidy to most other members of this genus. Two diterpene biosynthetic gene 
clusters were identified and are highly enriched in previously unidentified 
cytochrome P450s as well as crotonolide G synthase, which forms the dihydrofuran 
ring early in the SalA pathway. Coding sequences for other enzyme classes with 
likely involvement in downstream steps of the SalA pathway (BAHD acyl 
transferases, alcohol dehydrogenases, and O-methyl transferases) were scattered 
throughout the genome with no clear indication of clustering. Differential gene 
expression analysis suggests that most of these genes are not inducible by 
methyl jasmonate treatment.
CONCLUSIONS: This genome sequence and associated gene annotation are among the 
highest resolution in Salvia, a genus well known for the medicinal properties of 
its members. Here we have identified the cohort of genes responsible for the 
remaining steps in the SalA pathway. This genome sequence and associated 
candidate genes will facilitate the elucidation of SalA biosynthesis and enable 
an exploration of its full clinical potential.

© 2024. The Author(s).

DOI: 10.1186/s12870-024-05633-0
PMCID: PMC11443658
PMID: 39350001 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


4. J Ethnopharmacol. 2024 Dec 5;335:118697. doi: 10.1016/j.jep.2024.118697. Epub 
2024 Aug 16.

Salvinorin A ameliorates pilocarpine-induced seizures by regulating hippocampal 
microglia polarization.

Yang J(1), Cai JH(2), Wu TX(3), Gao ZQ(4), Zhou C(3), Wu Q(5), Ji MJ(6).

Author information:
(1)Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key 
Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key 
Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, 
School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China; 
Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 
200030, China.
(2)Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key 
Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key 
Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, 
School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China; 
Department of Anesthesiology, Sheyang County People's Hospital, Yancheng, 
224300, China. Electronic address: cjhtop1@163.com.
(3)Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key 
Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key 
Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, 
School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
(4)School of Pharmacology, Xuzhou Medical University, Xuzhou, 221004, China.
(5)Department of Physiology, Xuzhou Medical University, Xuzhou, 221004, China.
(6)Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key 
Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key 
Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, 
School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China. 
Electronic address: 100002018061@xzhmu.edu.cn.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum (Epling and Játiva) is a 
psychoactive plant traditionally used by the Latinos for various medicinal 
purposes. Salvinorin A (Sal A), the main bioactive constituent of S. divinorum, 
is a natural highly selective kappa opioid receptor (KOR) agonist. Considering 
the anti-inflammatory effect of S. divinorum and endogenous hippocampal 
dynorphin/kappa opioid receptor (KOR) system playing an anticonvulsant function, 
we hypothesis that Sal A can be a potential candidate to treat epilepsy. Here, 
we identified whether Sal A ameliorated epileptic seizures and neuronal damages 
in animal model and in vitro model and investigated its underlying mechanisms.
MATERIALS AND METHODS: Mice epilepsy model was induced by pilocarpine following 
seizures assessed by Racine classification. Hippocampus tissues were obtained 
for genetic, protein, and histological investigation. Furthermore, 
lipopolysaccharide (LPS)-activated BV2 microglial cells were utilized to 
validate the anti-inflammatory and microglia polarization regulation effects of 
Sal A.
RESULTS: Sal A treatment significantly prolonged the latency to status 
epileptics (SE) and shortened the duration of SE in the pilocarpine-induced 
model. It also alleviated neuronal damages via activation of the AMPK/JNK/p-38 
MAPK pathway and inhibition of apoptosis-related protein in hippocampus tissues. 
Furthermore, Sal A dose-dependently reduced microglia-mediated expression of 
pro-inflammatory cytokines and increased anti-inflammatory factors levels in SE 
mice and LPS-activated BV2 microglial cells by regulating microglia 
polarization. In addition, the effect of Sal A in vitro was totally blocked by 
KOR antagonist nor-BNI.
CONCLUSION: Sal A treatment protects against epileptic seizures and neuronal 
damages in pilocarpine-induced models by suppressing the inflammation response 
through regulating microglial M1/M2 polarization. This study might serve as a 
theoretical basis for clinical applications of Sal A and its analogs and provide 
a new insight into the development of anti-seizure drugs.

Copyright © 2024 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.jep.2024.118697
PMID: 39154669 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of competing interest The authors 
declare that there are no conflicts of interest.


5. J Med Chem. 2024 Aug 22;67(16):13788-13801. doi: 10.1021/acs.jmedchem.4c00590.
 Epub 2024 Aug 1.

Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid 
Receptor Determined by Salvinorin A-Based Virtual Screening.

Puls K(1), Olivé-Marti AL(2), Hongnak S(2), Lamp D(2), Spetea M(2), Wolber G(1).

Author information:
(1)Department of Pharmaceutical Chemistry, Institute of Pharmacy, Freie 
Universität Berlin, Königin-Luise-Str. 2-4, 14195 Berlin, Germany.
(2)Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for 
Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 
6020 Innsbruck, Austria.

Modulating the kappa-opioid receptor (KOR) is a promising strategy for treating 
various human diseases. KOR agonists show potential for treating pain, pruritus, 
and epilepsy, while KOR antagonists show potential for treating depression, 
anxiety, and addiction. The diterpenoid Salvinorin A (SalA), a secondary 
metabolite of Salvia divinorum, is a potent and selective KOR agonist. Unlike 
typical opioids, SalA lacks a basic nitrogen, which encouraged us to search for 
nonbasic KOR ligands. Through structure-based virtual screening using 3D 
pharmacophore models based on the binding mode of SalA, we identified novel, 
nonbasic, potent, and selective KOR agonists. In vitro studies confirmed two 
virtual hits, SalA-VS-07 and SalA-VS-08, as highly selective for the KOR and 
showing G protein-biased KOR agonist activity. Both KOR ligands share a novel 
spiro-moiety and a nonbasic scaffold. Our findings provide novel starting points 
for developing therapeutics aimed at treating pain and other conditions in which 
KOR is a central player.

DOI: 10.1021/acs.jmedchem.4c00590
PMCID: PMC11345774
PMID: 39088801 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing financial 
interest.