Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Drug Chem Toxicol. 2024 Aug 20:1-10. doi: 10.1080/01480545.2024.2389982.
Online  ahead of print.

Screening and toxicity evaluation of natural compounds as adenosine 2a and 2b 
receptor ligands: insights from molecular docking, dynamics, and ADMET analysis.

Karakuş F(1), Alagöz MA(2), Kuzu B(3).

Author information:
(1)Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Van Yuzuncu Yil 
University, Van, Türkiye.
(2)Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İnönü 
University, Malatya, Türkiye.
(3)Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Van Yuzuncu Yil 
University, Van, Türkiye.

Recent studies suggest that immunological and inflammatory responses in 
cardiovascular disorders, such as hypertension, myocardial infarction, ischemia 
injury, heart failure, arrhythmias, and atherosclerosis, may be affected by 
changes in the adenosine system. Pharmacological modulation of adenosine occurs 
through its receptor subtypes. In numerous preclinical studies, the activation 
of adenosine receptor 2A (A2AR) or the blockade of adenosine receptor 2B (A2BR) 
has shown promising results against cardiovascular diseases. This in silico 
study aimed to identify potential natural compounds that can activate A2AR or 
block A2BR without causing toxicity. Natural compounds were screened using 
COlleCtion of Open Natural ProdUcTs (COCONUT) or Natural Product Activity and 
Species Source Database (NPASS) databases to find agonists for A2AR or an 
antagonists/inverse agonists for A2BR. These compounds were then pre-filtered 
based on their toxicity profiles. The remaining compounds were subjected to 
molecular docking against A2AR and A2BR followed by molecular dynamics 
simulations were conducted. Finally, selected compounds' ADMET properties were 
determined using ADMETlab 2.0 web tool. Ultimately, one novel natural compound 
with potential agonistic activity (COCONUT IDs: CNP0450901) for A2AR and one 
antagonist/inverse agonist (rauwolscine) for A2BR were identified.

DOI: 10.1080/01480545.2024.2389982
PMID: 39165027


2. Int J Mol Sci. 2024 Jun 30;25(13):7233. doi: 10.3390/ijms25137233.

The Discovery of Novel α(2a) Adrenergic Receptor Agonists Only Coupling to Gαi/O 
Proteins by Virtual Screening.

Zhou P(1), Lu F(1), Zhu H(1), Shi B(1), Wang X(1), Sun S(1), Li Y(1), Su R(1).

Author information:
(1)State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key 
Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and 
Toxicology, 27th Taiping Road, Beijing 100850, China.

Most α2-AR agonists derived from dexmedetomidine have few structural differences 
between them and have no selectivity for α2A/2B-AR or Gi/Gs, which can lead to 
side effects in drugs. To obtain novel and potent α2A-AR agonists, we performed 
virtual screening for human α2A-AR and α2B-AR to find α2A-AR agonists with 
higher selectivity. Compound P300-2342 and its three analogs significantly 
decreased the locomotor activity of mice (p < 0.05). Furthermore, P300-2342 and 
its three analogs inhibited the binding of [3H] Rauwolscine with IC50 values of 
7.72 ± 0.76 and 12.23 ± 0.11 μM, respectively, to α2A-AR and α2B-AR. In 
α2A-AR-HEK293 cells, P300-2342 decreased forskolin-stimulated cAMP production 
without increasing cAMP production, which indicated that P300-2342 activated 
α2A-AR with coupling to the Gαi/o pathway but without Gαs coupling. P300-2342 
exhibited no agonist but slight antagonist activities in α2B-AR. Similar results 
were obtained for the analogs of P300-2342. The docking results showed that 
P300-2342 formed π-hydrogen bonds with Y394, V114 in α2A-AR, and V93 in α2B-AR. 
Three analogs of P300-2342 formed several π-hydrogen bonds with V114, Y196, F390 
in α2A-AR, and V93 in α2B-AR. We believe that these molecules can serve as leads 
for the further optimization of α2A-AR agonists with potentially few side 
effects.

DOI: 10.3390/ijms25137233
PMCID: PMC11241340
PMID: 39000340 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflicts of interest. 
The funders had no role in the design of the study; in the collection, analyses, 
or interpretation of data; in the writing of the manuscript; or in the decision 
to publish the results.


3. ACS Synth Biol. 2024 May 17;13(5):1498-1512. doi: 10.1021/acssynbio.4c00039. 
Epub 2024 Apr 18.

Yeast Platforms for Production and Screening of Bioactive Derivatives of 
Rauwolscine.

Bradley SA(1), Hansson FG(1), Lehka BJ(1), Rago D(1), Pinho P(1), Peng H(1), 
Adhikari KB(1), Haidar AK(1), Hansen LG(1)(2), Volkova D(1), Holtz M(1), Muyo 
Abad S(1), Ma X(1), Koudounas K(3), Besseau S(3), Gautron N(3), Mélin C(3), Marc 
J(3), Birer Williams C(3), Courdavault V(3), Jensen ED(1), Keasling 
JD(1)(4)(5)(6)(7), Zhang J(1)(2), Jensen MK(1)(2).

Author information:
(1)Novo Nordisk Foundation Center for Biosustainability, Technical University of 
Denmark, 2800 Lyngby, Denmark.
(2)Biomia ApS, DK-2100 Copenhagen, Denmark.
(3)EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, 
F-37200 Tours, France.
(4)Joint BioEnergy Institute, Emeryville, California 94608,United States.
(5)Biological Systems and Engineering Division, Lawrence Berkeley National 
Laboratory, Berkeley, California 94720,United States.
(6)Department of Chemical and Biomolecular Engineering, Department of 
Bioengineering, University of California, Berkeley, California 94720, United 
States.
(7)Center for Synthetic Biochemistry, Institute for Synthetic Biology, Shenzhen 
Institutes of Advanced Technologies, Shenzhen 518055, China.

Monoterpene indole alkaloids (MIAs) make up a highly bioactive class of 
metabolites produced by a range of tropical and subtropical plants. The 
corynanthe-type MIAs are a stereochemically complex subclass with therapeutic 
potential against a large number of indications including cancer, psychotic 
disorders, and erectile dysfunction. Here, we report yeast-based cell factories 
capable of de novo production of corynanthe-type MIAs rauwolscine, yohimbine, 
tetrahydroalstonine, and corynanthine. From this, we demonstrate regioselective 
biosynthesis of 4 fluorinated derivatives of these compounds and de novo 
biosynthesis of 7-chlororauwolscine by coexpression of a halogenase with the 
biosynthetic pathway. Finally, we capitalize on the ability of these cell 
factories to produce derivatives of these bioactive scaffolds to establish a 
proof-of-principle drug discovery pipeline in which the corynanthe-type MIAs are 
screened for bioactivity on human drug targets, expressed in yeast. In doing so, 
we identify antagonistic and agonistic behavior against the human adrenergic G 
protein-coupled receptors ADRA2A and ADRA2B, and the serotonergic receptor 
5HT4b, respectively. This study thus demonstrates a proto-drug discovery 
pipeline for bioactive plant-inspired small molecules based on one-pot 
biocatalysis of natural and new-to-nature corynanthe-type MIAs in yeast.

DOI: 10.1021/acssynbio.4c00039
PMID: 38635307 [Indexed for MEDLINE]


4. Commun Biol. 2023 Nov 24;6(1):1197. doi: 10.1038/s42003-023-05574-8.

The Rauvolfia tetraphylla genome suggests multiple distinct biosynthetic routes 
for yohimbane monoterpene indole alkaloids.

Stander EA(#)(1), Lehka B(#)(2), Carqueijeiro I(#)(1), Cuello C(#)(1), Hansson 
FG(#)(2), Jansen HJ(3), Dugé De Bernonville T(1)(4), Birer Williams C(1), Vergès 
V(1), Lezin E(1), Lorensen MDBB(5), Dang TT(6), Oudin A(1), Lanoue A(1), Durand 
M(1), Giglioli-Guivarc'h N(1), Janfelt C(5), Papon N(7), Dirks RP(3), O'connor 
SE(8), Jensen MK(9), Besseau S(10), Courdavault V(11).

Author information:
(1)Biomolécules et Biotechnologies Végétales, EA2106, Université de Tours, 
37200, Tours, France.
(2)Novo Nordisk Foundation Center for Biosustainability, Technical University of 
Denmark, Kgs, Lyngby, Denmark.
(3)Future Genomics Technologies, 2333 BE, Leiden, The Netherlands.
(4)Limagrain, Centre de Recherche, Route d'Ennezat, Chappes, France.
(5)Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
(6)Department of Chemistry, Irving K. Barber Faculty of Science, University of 
British Columbia, Kelowna, BC, Canada.
(7)Univ Angers, Univ Brest, IRF, SFR ICAT, F-49000, Angers, France.
(8)Department of Natural Product Biosynthesis, Max Planck Institute for Chemical 
Ecology, Jena, 07745, Germany. oconnor@ice.mpg.de.
(9)Novo Nordisk Foundation Center for Biosustainability, Technical University of 
Denmark, Kgs, Lyngby, Denmark. mije@dtu.dk.
(10)Biomolécules et Biotechnologies Végétales, EA2106, Université de Tours, 
37200, Tours, France. sebastien.besseau@univ-tours.fr.
(11)Biomolécules et Biotechnologies Végétales, EA2106, Université de Tours, 
37200, Tours, France. vincent.courdavault@univ-tours.fr.
(#)Contributed equally

Monoterpene indole alkaloids (MIAs) are a structurally diverse family of 
specialized metabolites mainly produced in Gentianales to cope with 
environmental challenges. Due to their pharmacological properties, the 
biosynthetic modalities of several MIA types have been elucidated but not that 
of the yohimbanes. Here, we combine metabolomics, proteomics, transcriptomics 
and genome sequencing of Rauvolfia tetraphylla with machine learning to discover 
the unexpected multiple actors of this natural product synthesis. We identify a 
medium chain dehydrogenase/reductase (MDR) that produces a mixture of four 
diastereomers of yohimbanes including the well-known yohimbine and rauwolscine. 
In addition to this multifunctional yohimbane synthase (YOS), an MDR 
synthesizing mainly heteroyohimbanes and the short chain dehydrogenase 
vitrosamine synthase also display a yohimbane synthase side activity. Lastly, we 
establish that the combination of geissoschizine synthase with at least three 
other MDRs also produces a yohimbane mixture thus shedding light on the complex 
mechanisms evolved for the synthesis of these plant bioactives.

© 2023. The Author(s).

DOI: 10.1038/s42003-023-05574-8
PMCID: PMC10673892
PMID: 38001233 [Indexed for MEDLINE]

Conflict of interest statement: R.D. and H.J. are CEO and CTO of Future Genomics 
Technologies, respectively. M.K.J. has a financial interest in Biomia. All other 
authors declare no competing interests.


5. Int J Mol Sci. 2022 Apr 13;23(8):4320. doi: 10.3390/ijms23084320.

Dexmedetomidine-Induced Aortic Contraction Involves Transactivation of the 
Epidermal Growth Factor Receptor in Rats.

Lee SH(1)(2)(3), Kwon SC(4), Ok SH(1)(2)(3), Ahn SH(5), Bae SI(5), Kim JY(5), 
Hwang Y(5), Park KE(5), Kim M(5), Sohn JT(3)(6).

Author information:
(1)Department of Anesthesiology and Pain Medicine, Gyeongsang National 
University Changwon Hospital 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, 
Gyeongsangnam-do, Korea.
(2)Department of Anesthesiology and Pain Medicine, Gyeongsang National 
University College of Medicine, 15 Jinju-daero 816 beon-gil, Jinju-si 52727, 
Gyeongsangnam-do, Korea.
(3)Institute of Health Sciences, Gyeongsang National University, Jinju-si 52727, 
Gyeongsangnam-do, Korea.
(4)Department of Physiology, Institute of Clinical and Translational Research, 
Catholic Kwandong University, College of Medicine, Gangneung 25601, Korea.
(5)Department of Anesthesiology and Pain Medicine, Gyeongsang National 
University Hospital, 15 Jinju-daero 816 beon-gil, Jinju-si 52727, 
Gyeongsangnam-do, Korea.
(6)Department of Anesthesiology and Pain Medicine, Gyeongsang National 
University College of Medicine, Gyeongsang National University Hospital, 15 
Jinju-daero 816 beon-gil, Jinju-si 52727, Gyeongsangnam-do, Korea.

In this study, we examined whether aortic contraction, induced by the alpha-2 
adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the 
epidermal growth factor receptor (EGFR) in isolated endothelium-denuded rat 
aortas. Additionally, we aimed to elucidate the associated underlying cellular 
mechanisms. The effects of the alpha-2 adrenoceptor inhibitor rauwolscine, EGFR 
tyrosine kinase inhibitor AG1478, Src kinase inhibitors PP1 and PP2, and matrix 
metalloproteinase inhibitor GM6001 on EGFR tyrosine phosphorylation and c-Jun 
NH2-terminal kinase (JNK) phosphorylation induced by dexmedetomidine in rat 
aortic smooth muscles were examined. In addition, the effects of these 
inhibitors on dexmedetomidine-induced contraction in isolated 
endothelium-denuded rat aorta were examined. Dexmedetomidine-induced contraction 
was inhibited by the alpha-1 adrenoceptor inhibitor prazosin, rauwolscine, 
AG1478, PP1, PP2, and GM6001 alone or by a combined treatment with prazosin and 
AG1478. AG1478 (3 × 10-6 M) inhibited dexmedetomidine-induced contraction in 
isolated endothelium-denuded rat aortas pretreated with rauwolscine. 
Dexmedetomidine-induced EGFR tyrosine and JNK phosphorylation were inhibited by 
rauwolscine, PP1, PP2, GM6001, and AG1478. Furthermore, dexmedetomidine-induced 
JNK phosphorylation reduced upon EGFR siRNA treatment. Therefore, these results 
suggested that the transactivation of EGFR associated with 
dexmedetomidine-induced contraction, mediated by the alpha-2 adrenoceptor, Src 
kinase, and matrix metalloproteinase, caused JNK phosphorylation and increased 
calcium levels.

DOI: 10.3390/ijms23084320
PMCID: PMC9024600
PMID: 35457136 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest. The 
funders had no role in the study design; in the collection, analyses, or 
interpretation of data; in the writing of the manuscript; or in the decision to 
publish the results.