Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. J Agric Food Chem. 2024 Mar 13;72(10):5403-5415. doi:
10.1021/acs.jafc.3c09142.  Epub 2024 Feb 22.

Decoding Molecular Mechanism Underlying Human Olfactory Receptor OR8D1 
Activation by Sotolone Enantiomers.

Wang J(1)(2)(3), Wang D(1)(2), Huang M(1)(2), Sun B(1)(2)(3), Ren F(3), Wu 
J(1)(2), Zhang J(1)(2), Li H(1)(2), Sun X(1)(2).

Author information:
(1)Key Laboratory of Brewing Molecular Engineering of China Light Industry, 
Beijing Technology & Business University (BTBU), Beijing 100048, China.
(2)Key Laboratory of Geriatric Nutrition and Health, Beijing Technology and 
Business University, Ministry of Education, Beijing 100048, China.
(3)Beijing Advanced Innovation Center for Food Nutrition and Human Health, 
Department of Nutrition and Health, China Agricultural University, Beijing 
100193, China.

Sotolone, a chiral compound, plays an important role in the food industry. 
Herein, (R)-/(S)-sotolone were separated to determine their odor characteristics 
and thresholds in air (R-form: smoky, burned, herb, and green aroma, 0.0514 
μg/m3; S-form: sweet, milk, acid, and nutty aroma, 0.0048 μg/m3). OR8D1 
responses to (R)-/(S)-sotolone were detected in a HEK293 cell-based luminescence 
assay. (S)-Sotolone was a more potent agonist than (R)-sotolone (EC50 values of 
84.98 ± 1.05 and 167.20 ± 0.25 μmol/L, respectively). Molecular dynamics 
simulations and molecular mechanics Poisson-Boltzmann surface area analyses 
confirmed that the combination of (S)-sotolone and OR8D1 was more stable than 
that of (R)-sotolone. Odorant docking, multiple sequence alignments, 
site-directed mutagenesis, and functional studies with recombinant odorant 
receptors (ORs) in a cell-based luminescence assay identified 11 amino-acid 
residues that influence the enantioselectivity of OR8D1 toward sotolone 
significantly and that N2065.46 was indispensable to the activation of OR8D1 by 
(S)-sotolone.

DOI: 10.1021/acs.jafc.3c09142
PMID: 38386648 [Indexed for MEDLINE]


2. J Agric Food Chem. 2022 May 11;70(18):5756-5763. doi:
10.1021/acs.jafc.2c01480.  Epub 2022 Apr 28.

Quantitative Analysis of Lactone Enantiomers in Butter and Margarine through the 
Combination of Solvent Extraction and Enantioselective Gas Chromatography-Mass 
Spectrometry.

Saeki R(1), Yoshinaga K(2), Tago A(1), Tanaka S(1), Yoshinaga-Kiriake A(2)(3), 
Nagai T(4), Yoshida A(4), Gotoh N(1).

Author information:
(1)Department of Food Science and Technology, Tokyo University of Marine Science 
and Technology, 4-5-7 Konan, Minato-ku, Tokyo 108-8477, Japan.
(2)Faculty of Food and Agricultural Sciences, Fukushima University, 1 
Kanayagawa, Fukushima 960-1296, Japan.
(3)Department of Life Science, Graduate School of Engineering Science, Akita 
University, 1-1 Tegatagakuen-machi, Akita 010-8502, Japan.
(4)Tsukishima Foods Industry Co. Ltd., 3-17-9 Higashi Kasai, Edogawa-ku, Tokyo 
134-8520, Japan.

Erratum in
    J Agric Food Chem. 2022 Aug 3;70(30):9596. doi: 10.1021/acs.jafc.2c03868.

We quantified the enantiomeric distributions of δ- and γ-lactones in butter, 
fermented butter, and margarine through the combination of solvent extraction 
and enantioselective gas chromatography-mass spectrometry. The main lactones in 
butter and fermented butter comprised (R)-δ-decalactone, (R)-δ-dodecalactone, 
(R)-δ-tetradecalactone, (R)-δ-hexadecalactone, and (R)-γ-dodecalactone. In 
contrast, margarine samples consisted of only δ-decalactone and δ-dodecalactone 
in racemic forms, indicating that synthetic aroma chemicals were added to 
margarine. After heat treatment, 13 types of lactones were detected in butter 
and fermented butter. In heated butter and fermented butter, major δ-lactones in 
the (R)-form were abundant, but only δ-octalactone in the (S)-form was detected. 
In contrast, γ-dodecalactone (main γ-lactone in the heated samples) was abundant 
in the (R)-form, whereas other γ-lactones were detected in the racemic form. 
These results suggested that the major lactones in dairy products are in the 
(R)-form. Furthermore, the heat treatment affected the enantiomeric distribution 
of lactones in butter and fermented butter.

DOI: 10.1021/acs.jafc.2c01480
PMID: 35482605 [Indexed for MEDLINE]


3. Neuropharmacology. 2020 Apr;166:107718. doi: 10.1016/j.neuropharm.2019.107718.
 Epub 2019 Jul 24.

Biased agonism of clinically approved μ-opioid receptor agonists and TRV130 is 
not controlled by binding and signaling kinetics.

Pedersen MF(1), Wróbel TM(2), Märcher-Rørsted E(3), Pedersen DS(3), Møller 
TC(3), Gabriele F(3), Pedersen H(4), Matosiuk D(5), Foster SR(3), Bouvier M(6), 
Bräuner-Osborne H(7).

Author information:
(1)Department of Drug Design and Pharmacology, University of Copenhagen, 
Copenhagen, Denmark; Department of Biochemistry and Molecular Medicine, 
Institute for Research in Immunology and Cancer, Université de Montréal, 
Montreal, QC, Canada.
(2)Department of Drug Design and Pharmacology, University of Copenhagen, 
Copenhagen, Denmark; Department of Synthesis and Chemical Technology of 
Pharmaceutical Substances, Medical University of Lublin, Lublin, Poland.
(3)Department of Drug Design and Pharmacology, University of Copenhagen, 
Copenhagen, Denmark.
(4)Lundbeck A/S, Valby, Denmark.
(5)Department of Synthesis and Chemical Technology of Pharmaceutical Substances, 
Medical University of Lublin, Lublin, Poland.
(6)Department of Biochemistry and Molecular Medicine, Institute for Research in 
Immunology and Cancer, Université de Montréal, Montreal, QC, Canada. Electronic 
address: michel.bouvier@umontreal.ca.
(7)Department of Drug Design and Pharmacology, University of Copenhagen, 
Copenhagen, Denmark. Electronic address: hbo@sund.ku.dk.

Binding and signaling kinetics have previously proven important in validation of 
biased agonism at GPCRs. Here we provide a comprehensive kinetic pharmacological 
comparison of clinically relevant μ-opioid receptor agonists, including the 
novel biased agonist oliceridine (TRV130) which is in clinical trial for pain 
management. We demonstrate that the bias profile observed for the selected 
agonists is not time-dependent and that agonists with dramatic differences in 
their binding kinetic properties can display the same degree of bias. Binding 
kinetics analyses demonstrate that buprenorphine has 18-fold higher receptor 
residence time than oliceridine. This is thus the largest pharmacodynamic 
difference between the clinically approved drug buprenorphine and the clinical 
candidate oliceridine, since their bias profiles are similar. Further, we 
provide the first pharmacological characterization of (S)-TRV130 demonstrating 
that it has a similar pharmacological profile as the (R)-form, oliceridine, but 
displays 90-fold lower potency than the (R)-form. This difference is driven by a 
significantly slower association rate. Finally, we show that the selected 
agonists are differentially affected by G protein-coupled receptor kinase 2 and 
5 (GRK2 and GRK5) expression. GRK2 and GRK5 overexpression greatly increased 
μ-opioid receptor internalization induced by morphine, but only had modest 
effects on buprenorphine and oliceridine-induced internalization. Overall, our 
data reveal that the clinically available drug buprenorphine displays a similar 
pharmacological bias profile in vitro compared to the clinical candidate drug 
oliceridine and that this bias is independent of binding kinetics suggesting a 
mechanism driven by receptor-conformations. This article is part of the Special 
Issue entitled 'New Vistas in Opioid Pharmacology'.

Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/j.neuropharm.2019.107718
PMID: 31351108 [Indexed for MEDLINE]


4. Am J Cardiovasc Drugs. 2014 Feb;14(1):63-72. doi: 10.1007/s40256-013-0051-2.

Pharmacokinetics, tolerability, and safety of the single oral administration of 
AGSAV301 vs Exforge: a randomized crossover study of healthy male volunteers.

Choi HY(1), Kim YH, Kim MJ, Noh YH, Lee SH, Bae KS, Lim HS.

Author information:
(1)Department of Clinical Pharmacology and Therapeutics, College of Medicine, 
University of Ulsan, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, 
Seoul, 138-736, Korea.

BACKGROUND AND OBJECTIVE: Valsartan, an angiotensin receptor blocker, is often 
used with calcium channel blockers (CCBs) such as amlodipine to control 
hypertension. Recently, the fixed-dose combination (FDC) of amlodipine 
10 mg/valsartan 160 mg (Exforge) was approved. Amlodipine is a racemic mixture 
of CCB; S-amlodipine has higher activity than R-form. Therefore, AGSAV301, the 
FDC of S-amlodipine 5 mg/valsartan 160 mg was recently developed. The objective 
of this study was to compare the pharmacokinetic (PK) characteristics of 
S-amlodipine and valsartan when administered as one tablet each of Exforge and 
AGSAV301 to healthy male subjects.
METHODS: This was a single-dose, randomized, open-label, two-way, two-period 
crossover study. Each subject received a single dose of AGSAV301 and Exforge, 
separated by a 3-week washout period. Plasma samples for the PK analysis of 
valsartan and S-amlodipine were collected at predose (0) and 0.5, 1, 2, 3, 4, 5, 
6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 168 h after administration. 
Tolerability was also evaluated.
RESULTS: A total of 29 subjects were enrolled; 24 completed this study. The 
S-amlodipine maximum plasma concentration (C max) geometric mean ratio (GMR) 
between AGSAV301 and Exforge was 0.951 (90 % CI 0.983-1.014), and area under the 
concentration-time curve from time 0 to last measured time point (AUClast) was 
0.917 (90 % CI 0.861-0.976). The GMR of valsartan C max was 0.994 (90 % CI 
0.918-1.076), and the AUClast was 0.927 (90 % CI 0.821-1.047). All adverse 
events (AEs) were resolved without sequelae; no serious AEs were reported. Two 
drugs showed similar tendencies to lower blood pressure in healthy subjects.
CONCLUSIONS: The PK profiles of AGSAV301 and Exforge were bioequivalent. Both 
drugs were also well tolerated, with comparable AE profiles and similar blood 
pressure-lowering tendencies in healthy volunteers, suggesting equivalent 
therapeutic indications.

DOI: 10.1007/s40256-013-0051-2
PMID: 24174172 [Indexed for MEDLINE]


5. J Agric Food Chem. 2012 Feb 15;60(6):1503-9. doi: 10.1021/jf204378u. Epub 2012
 Feb 6.

Distribution and organoleptic impact of ethyl 2-hydroxy-4-methylpentanoate 
enantiomers in wine.

Lytra G(1), Tempere S, de Revel G, Barbe JC.

Author information:
(1)Université Bordeaux, ISVV, EA 4577 Œnologie, 33882 Villenave d'Ornon, France.

The enantiomers of ethyl 2-hydroxy-4-methylpentanoate (ethyl dl-leucate) were 
assayed in several wines using chiral gas chromatography (γ-cyclodextrin). 
Analyses of 55 commercial wines from various vintages and origins revealed 
different distributions. Generally, white wines presented only the R form, 
whereas red wines contained both enantiomers, in various ratios according to 
aging. The highest levels of the S form were found in the oldest samples. The 
R/S average enantiomeric ratio of this compound in red wine was approximately 
95:5 with an average total concentration of ∼400 μg/L. The olfactory threshold 
of R-ethyl 2-hydroxy-4-methylpentanoate (126 μg/L) in hydroalcoholic solution 
was almost twice that of the S form (55 μg/L). The olfactory threshold of a 
mixture of R- and S-ethyl 2-hydroxy-4-ethylpentanoate (95:5, m/m) in 
hydroalcoholic solution was 51 μg/L, suggesting that both enantiomeric forms 
contribute to perception of this compound in wine, resulting in a synergistic 
effect. Both enantiomers have quite similar aromatic nuances. Sensory analysis 
was employed to demonstrate a synergistic effect of this ethyl ester on the 
perception of fruity aromas in wine: in hydroalcoholic solution supplemented 
with R- or S-ethyl 2-hydroxy-4-methylpentanoate or a mixture of the R and S 
forms (95:5, m/m) at their average concentrations in red wines, fruity character 
was perceived at concentrations 2.2, 4.5, and 2.5 times lower, respectively, 
than in hydroalcoholic solution alone. Sensory profiles of aromatic 
reconstitutions, using HPLC fruity fractions, highlighted the contribution of 
this compound to blackberry fruit and fresh fruit descriptors.

DOI: 10.1021/jf204378u
PMID: 22224424 [Indexed for MEDLINE]