•New potential Michael acceptor analogues of salvinorin A were synthesized.•Compounds were evaluated for binding affinity at κ-, δ-, and μ-opioid receptors.•Molecular modeling studies describe putative binding modes for the compounds.•Most compounds have high binding affinity at κ; 5a has dual affinity for κ and μ.•5a could be developed as a potent CNS or peripheral drug in the near future.The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand–receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure–activity relationships, and previous salvinorin A–KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.

Salvia divinorum—a species traditionally cultivated in Oaxaca, Mexico—possesses hallucinogenic properties. It is legally recognized as a controlled substance and prohibited in many countries. The proper identification of the plant, both in fresh and dried forms, is an important issue in crime-prevention campaigns. This paper provides a thorough anatomical description of leaves, petioles, and stems of S. divinorum. Detailed investigation of foliar trichomes was performed and illustrated. In addition, chromatographic analyses, including TLC and HPLC, were applied to fresh and dried plant material, together with the standard reference salvinorin A. A comprehensive identification method for S. divinorum based on a thorough anatomical examination is proposed, combined with chemical analysis for proper plant recognition.

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki’s as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety–depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.

Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective κ-opioid receptor agonist. To better understand the ligand–receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at κ-, δ- and μ-opioid receptors. Most of the analogues show high affinity to the κ-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (Ki = 2 nM), analogues 5, 7, and 14 exhibit significant affinity for the κ-receptor (Ki = 21, 36 and 39 nM).

Highlights► Four triterpenoids and nine flavonoids were isolated from Cecropia schreberiana. ► Oleanane triterpenoid and flavanolignans are reported first time from the Urticaceae. ► The study supports the common occurrence of flavanolignans within Magnoliopsida.

Three known (leoleorins A–C) and eight hitherto unknown (leoleorins D-J and 16-epi-leoleorin F) labdane diterpenoids, were isolated from leaves of Leonotis leonurus. The absolute configurations of leoleorins A and D were established by X-ray crystallographic analyses. In a competitive binding assay, all isolated compounds showed inhibition in excess of 50% at various CNS receptors. Leoleorin C showed moderate binding affinity (Ki = 2.9 μM) for the Sigma 1 receptor.Graphical abstractEight labdane diterpenoids shown below together with three known compounds, were isolated from leaves of Leonotis leonurus. Their interactions with CNS G-protein-coupled receptors were evaluated.Highlights► Eleven labdane diterpenoids were isolated from the leaves of Leonotis leonurus. ► Eight compounds were hitherto unknown. ► All compounds were evaluated for their binding affinities to various CNS receptors. ► Leoleorin C (11) showed weak binding affinity (Ki = 2.9 μM) to the Sigma 1 receptor.

Ten new bis-spirolabdane diterpenoids, leonepetaefolins A–E (1, 3, 5, 7, 9) and 15-epi-leonepetaefolins A–E (2, 4, 6, 8, 10), together with eight known labdane diterpenoids (11–18) as well as two known flavonoids, apigenin and cirsiliol, were isolated from the leaves of Leonotis nepetaefolia. The structures of the new compounds were determined on the basis of 1D- and 2D-NMR experiments including 1H, 13C, DEPT, 1H–1H COSY, HSQC, HMBC, and NOESY. The absolute configuration of an epimeric mixture of 1 and 2 was determined by X-ray crystallographic analysis. The compounds isolated were evaluated for their binding propensity in several CNS G-protein-coupled receptor assays in vitro.

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-imino-1,3-dimethylimidazolidin-4-one (3x) possessed an IC50 of 5.6 nM at MAO-A and had a selectivity index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position N-2′, and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.

Six new labdane diterpenoids, preleosibirone A (1), 13-epi-preleosibirone A (2), isopreleosibirone A (3), leosibirone A (4), leosibirone B (5), and 15-epi-leosibirone B (6), were isolated from the leaves of Leonurus sibiricus. The absolute configurations of 1, 2, 5, and 6 were established by X-ray crystallographic analyses, and leosibirone A (4) was shown to be an artifact of the isolation process.

The synthesis and in vitro evaluation of a new series of salvinorin A analogues substituted at the C(2) position with natural amino acids is reported. Compound 12, containing Val, displayed high affinity and full agonist activity at the kappa-opioid receptor. Analogues with bulky and/or aromatic residues were inactive, showing the importance of size and electronegativity of C(2)-substituents for binding affinity of salvinorin A derivatives.

Extraction of fresh Salvia divinorum leaves afforded salvinorins E and D as potential biosynthesis precursors of salvinorin A, a major metabolite and a potent hallucinogen. Attempts at HPLC purification of salvinorin E (2) with acetonitrile as a solvent revealed an equilibrium with its regioisomer, salvinorin D (3), in a 3:5 ratio. The presence of both compounds was readily observed in the 1H NMR spectrum. This spontaneous formation of the mixture of isomers occurs via a dynamic intramolecular transacetylation process.

A search for biosynthetic precursors of salvinorin A (1) led to the isolation of a new neoclerodane diterpenoid hemiacetal mixture, salvinorins J (2), from the chloroform extract of Salvia divinorum. A leaf surface extraction method was used on S. divinorum, affording a chlorophyll-free extract containing predominantly neoclerodane diterpenoids, including the new salvinorins J (2) and 14 known analogues. Salvinorins J (2) represent an example of a neoclerodane hemiacetal (lactol) susceptible to mutarotation with the formation of an equilibrium mixture of C-17 epimers.

To study drug-receptor interactions, new thio-derivatives of salvinorin A, an extremely potent natural κ-opioid receptor (KOR) agonist, were synthesized. Obtained compounds were examined for receptor binding affinity. Analogs with the same configuration at carbon atom C-2 as in natural salvinorin A showed higher affinity to KOR than their corresponding epimers.To study drug-receptor interactions, new thio-derivatives of salvinorin A, an extremely potent natural κ-opioid receptor agonist, were synthesized and examined for receptor binding affinity.

Salvinorin A, a neoclerodane diterpenoid, isolated from the Mexican hallucinogenic plant Salvia divinorum, is a potent kappa-opioid receptor agonist. Its biosynthetic route was studied by NMR and HR-ESI-MS analysis of the products of the incorporation of [1-13C]-glucose, [Me-13C]-methionine, and [1-13C; 3,4-2H2]-1-deoxy-d-xylulose into its structure. While the use of cuttings and direct-stem injection were unsuccessful, incorporation of 13C into salvinorin A was achieved using in vitro sterile culture of microshoots. NMR spectroscopic analysis of salvinorin A (2.7 mg) isolated from 200 microshoots grown in the presence of [1-13C]-glucose established that this pharmacologically important diterpene is biosynthesized via the 1-deoxy-d-xylulose-5-phosphate pathway, instead of the classic mevalonic acid pathway. This was confirmed further in plants grown in the presence of [1-13C; 3,4-2H2]-1-deoxy-d-xylulose. In addition, analysis of salvinorin A produced by plants grown in the presence of [Me-13C]-methionine indicates that methylation of the C-4 carboxyl group is catalyzed by a type III S-adenosyl-l-methionine-dependent O-methyltransferase.Biosynthetic analysis of diterpene salvinorin A proved its formation via the DOXP pathway. Salvia divinorum was administered [1-13C]-d-glucose in sterile culture of microshoots. Results were analyzed by LCMS and NMR spectroscopic techniques.