Ring System Research Articles

Identification of three novel P450 enzymes involved in the oxidative modification of a newly discovered fusicoccane diterpene

Fusicoccane (FC)-type diterpenoids are a class of diterpenoids characterized by a unique 5–8–5 ring system and exhibit diverse biological activities. Recently, we identified a novel FC-type diterpene synthase MgMS, which produces a myrothec-15(17)-en-7-ol (1) hydrocarbon skeleton, however, its tailoring congeners have not been elucidated. Here, we discovered two additional gene clusters Bn and Np, each encoding a highly homologous terpene synthase to MgMS but distinct tailoring enzymes. Heterologous expression of the terpene synthases BnMS and NpMS yielded the same product as MgMS. Subsequent introduction of three P450 enzymes MgP450, BnP450 and NpP450 from individual gene clusters resulted in four new FC-type diterpenoids 2–5. Notably, MgP450 serves as the first enzyme responsible for hydroxylation of the C19 methyl group, whereas NpP450 functions as a multifunctional P450 enzyme involved in the oxidations at C5, C6, and C19 positions of the 5–8–5 tricyclic skeleton. C5 oxidation of the hydrocarbon skeleton 1 led to broadening of the NMR signals and incomplete spectra, which was resolved by high-temperature NMR spectral analysis.

Acetylcholinesterase inhibitory phloroglucinols from tropic Rhodomyrtus tomentosa

Four previously undescribed phloroglucinols, including three pairs of enantiomers, (±)-rhodotomentodimer F, (±)-rhodotomentodimer G, and (±)-rhodotomentomonomer E, and one phloroglucinol-sesquiterpene meroterpenoid, rhodotomentodione E, together with one previously reported congener, (±)-rhodomyrtosone A, were obtained from the leaves of Rhodomyrtus tomentosa. The structures including absolute configurations of previously undescribed isolates were elucidated by extensive spectroscopic analysis (HRESIMS and NMR), ECD calculations, and single-crystal X-ray diffraction. (±)-Rhodotomentodimer F is a rare phloroglucinol derivative conjugated by a β-triketone moiety and an unprecedented resorcinol unit via the formation of a rare bis-furan ring system, whereas (±)-rhodotomentomonomer E shares a rearranged pentacyclic scaffold. Pharmacologically, (±)-rhodotomentomonomer E showed the strongest human acetylcholinesterase (hAChE) inhibitory effect with an IC50 value of 1.04 ± 0.05 μM. Molecular formula studies revealed that hydrogen bonds formed between hAChE residues Glu202, Ser203, Ala204, Gly121, Gly122, Tyr337, and His447 and (±)-rhodotomentomonomer E played crucial roles in its observed activity. These findings indicated that the leaves of Rhodomyrtus tomentosa can supply a rich source of hAChE inhibitors. These inhibitors might potentially be utilized in the therapeutic strategy for Alzheimer's disease, offering promising candidates for further research and development.

Chiral superficially porous stationary phases for enantiomeric separation of condensed 1,4-dihydropyridine derivatives

1,4-dihydropyridine (DHP) scaffold occupies a prominent position among all heterocyclic compounds owing to its versatile pharmacological properties, particularly its well-known calcium channel blocking activity. In the quest of developing new calcium channel blockers, fifty seven 5-oxo-hexahydroquinoline (HHQ) derivatives carrying DHP framework in a condensed ring system were recently synthesized as racemic mixtures. Due to their potential as drug candidates, enantiomers arising from the asymmetric center at the C-4 position of the HHQ ring were separated. Four modern columns packed with 2.7 µm superficially porous particles bonded with a chiral selector were used. The chiral selectors were three macrocyclic glycopeptide selectors: vancomycin, teicoplanin, and a macrocyclic derivative called nico. The fourth bonded selector was the dinitrobenzamido-tetrahydrophenanthrenyl derivative called Whelko. The four chromatographic modes were assayed with the mobile phase compositions: reversed phase with acetonitrile/buffer 30/70 %v/v, normal phase with hexane/ethanol 80/20 %v/v, and subcritical fluid chromatography with CO2/methanol 80/20 %v/v at 25 °C. The WhelkoShell column was the most effective in separating this set of 57 compounds. Several enantioresolution factors passed 20 with enantioselectivity ratios higher than 4. Molecular modeling showed that the compounds had a T-shape that fitted well the molecular structure of the WhelkoShell selector in the normal or subcritical modes. Additionally, seven compounds had a second chiral center. The NicoShell column was able to separate all four stereoisomers of these compounds in the reversed phase mode. The preparative production of pure enantiomers of these compounds would be straightforward using the WhelkoShell column in the subcritical mode.

Catalytic Activity of an Asymmetric Uranyl‐Salophen on 2,4‐Dichlorophenol, 2,4,6‐Trichlorophenol, and Pentachlorophenol

ABSTRACTThis study employs density functional theory to investigate whether asymmetric uranyl‐Salophen catalyzes the activation of 2,4‐dichlorophenol, 2,4,6‐trichlorophenol, and pentachlorophenol. Changes in various important parameters such as bond lengths, Wiberg bond indices, infrared vibrational absorption spectra, natural charge distributions, ultraviolet–visible absorption spectra, and 13C NMR chemical shifts of the aromatic rings of chlorophenols before and after forming complexes with asymmetric uranyl‐Salophen are analyzed. This means that asymmetric uranyl‐Salophen indeed activates 2,4‐dichlorophenol, 2,4, 6‐trichlorophenol, and pentachlorophenol, significantly lengthening the aromatic ring bonds of the three chlorophenols and increasing the electrophilicity of the carbon atoms in the aromatic ring. This suggests that the conjugated system of the aromatic ring is also partially disrupted, indicating that these three chlorophenols are indeed catalytically activated. Furthermore, this implies that this asymmetric uranyl‐Salophen may be used to degrade chlorophenols in water.

Synthesis of various dihydro‐thiazole and selenazole heterocycles

We prepared numerous thiazole derivatives from push‐pull alkenes such as nitroenamines, enaminoester, and enaminonitrils in a two‐step reaction with thiocyanate ion. The first step was the formation of the thiocyanate‐substituted push‐pull alkene from an iodine‐containing intermediary. We demonstrated this sequence through the preparation and identification of the iodine‐substituted enamines. In the second step, thiazole ring closure took place in methanol, at room temperature. The imino group of the condensed thiazole ring systems was successfully acylated. The same reaction sequence with potassium selenocyanate resulted in two selenocyanate and a selenazole heterocyclic derivatives. The mechanism of the reaction with thiocyanate ion and the heterocycle formation was investigated by computational methods. We performed quantum chemical calculations, involving both the thermodynamic and the kinetic aspects of the ring closure reaction.

Recent Innovations in Synthetic Methodologies and Patent Landscape of Quinoline Analogues: A Comprehensive Review

: Quinoline is a general group of heterocyclic compounds that have garnered much interest in medicinal chemistry and drug development due to their wide range of pharmacological effects. Pyridine ring fused with benzene defines the class of chemical compounds known as quinolines. Quinoline is a weak tertiary base, also known as 1-aza-naphthalene. Numerous patents have been filed for the synthesis of quinoline-based compounds, discussing about their derivatives and uses. Here, we have discussed the methods of quinoline synthesis, structural alterations, and patents showing its importance in various industries. Quinolines have been investigated as antimalarial substances, with substances, like quinine and chloroquine, serving as notable examples, and they have also been investigated to possess anti-inflammatory, anti-tumor, and CNS activity. The synthesis of quinoline is also subjected to several recognized procedures. The variations in the ring system and various synthetic approaches are the key highlights of the article, and it includes the various catalysts that could be recycled and reused by the assisted technique, which increases the yield and requires less time for the synthesis (ultrasound-promoted synthesis, one-pot reaction, and microwave and photocatalytic reactions). The development of synthetic procedures can help in the sustainable synthesis of quinoline derivatives.

Skeletal Transformations Observed in the Reaction of a Tricyclic Thymine Nucleoside with Dicarbonyl Compounds.

Some intriguing skeletal transformations were observed in the reaction of α-hydroxypyrrolidine thymine nucleoside 2 with different dicarbonyl compounds. In these reactions, unusual ring systems, together with new C-C bonds and stereogenic centers of defined configuration, were formed in a single step. These reactions were initiated by the nucleophilic attack of the NH of the pyrrolidine ring, present on 2, on one of the carbonyl moieties of a dicarbonyl reagent and seem to proceed through an enamine-iminium mechanism. The present methodology is particularly attractive because no catalyst or aggressive conditions are needed. The new polycyclic nucleosides obtained from 2 can be good scaffolds for diversification. In fact, modification and derivatization can be achieved by performing further chemical transformations of the functional groups present in some of them. This may lead to the formation of new highly functionalized nucleosides. Our results show the high synthetic potential of 2 to construct complex systems in an efficient way. On the other hand, the enamine chemistry involved in the particular reactivity of the α-hydroxy pyrrolidine ring present in 2 has no connection with the nucleobase and could be extended to simple glycosides preserving this essential ring system.

Spectral signatures of solvent-extracted macromolecules in Indian coals of different rank: Insights from fluorescence excitation-emission matrix

Solvent-extracted fractions of six Indian coal samples of different ranks were investigated using multiple geochemical, petrological and spectroscopic proxies and an attempt was made to indicate possible fingerprint regions for different polycyclic aromatic hydrocarbons (PAH) with the help of excitation-emission matrix (EEM). In this study, for the very first time, the influence of rank and maturation of organic matter in the characterisation of coal solvent-extracts from Indian coals were perceived from the viewpoint of fluorescence EEM. Vitrinite reflectance (VRo) values were used to determine the general ranks of the original coal samples viz. lignite, subbituminous, bituminous and anthracite. Different fluorescence peak regions corresponding to different fused aromatic ring (FAR) systems were delineated using the EEM and their indicative depositional environments could be inferred. Our observations indicate that solvent-extracted fractions of low rank coals comprise of a larger number of shorter carbon chains compared to the other samples. For the low rank coal samples, the solvent-extracts show a strong humic influence and the presence of smaller PAH rings while for the medium rank coals, the extracted fractions tend to show a more bimodal distribution of PAHs, possibly comprising of different sized PAHs. Higher fluorescence sensitivity and quick response of smaller PAHs impart a singular centralised region in the EEM for the low rank coal samples while interference in the fluorescence of differently sized PAHs indicate a multimodal distribution of the fluorophores in the medium rank coals. The high rank coal used in this study shows a bimodal distribution with very low intensity of the peaks, indicating the low abundance of extractable macromolecules, possibly as a result of deformation.

Exploring the Darobactin Class of Antibiotics: A Comprehensive Review from Discovery to Recent Advancements.

The prevalence of antimicrobial resistance in Gram-negative bacteria poses a greater challenge due to their intrinsic resistance to many antibiotics. Recently, darobactins have emerged as a novel class of antibiotics originating from previously unexplored Gram-negative bacterial species such as Photorhabdus, Vibrio, Pseudoalteromonas and Yersinia. Darobactins belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) class of antibiotics, exhibiting selective activity against Gram-negative bacteria. They target the β-barrel assembly machinery (BAM), which is crucial for the maturation and insertion of outer membrane proteins in Gram-negative bacteria. The dar operon in the producer's genome encodes for the synthesis of darobactins, which are characterized by a fused ring system connected via an alkyl-aryl ether linkage (C-O-C) and a C-C cross-link. The enzyme DarE, using the radical S-adenosyl-l-methionine (rSAM), facilitates the formation of these bonds. Biosynthetic manipulation of the darobactin gene cluster, along with its expression in a surrogate host, has enabled access to diverse darobactin analogues with variable antibiotic activities. Recently, two independent research groups successfully achieved the total synthesis of darobactin, employing Larock heteroannulation to construct the bicyclic structure. This paper presents a comprehensive review of darobactins, encompassing their discovery through to the most recent advancements.

Electrocatalytic Radical Cation Diels-Alder Reactions Using Enol Ethers As Dienophiles

Single-electron oxidation enables the conversion of electron-rich alkenes such as styrene derivatives to radical cation species. We have been developing various cycloaddition reactions of radical cations produced by single-electron oxidation using electrochemical and TiO2 photochemical methods. Introducing an electron-rich aryl group which we call a redox tag is a critical part of the process to control the reactivity of the radical cations. During carbon-carbon bonds formation the motif functions as both electron donor and electron acceptor. In addition to styrene derivatives, enol ethers can also be readily oxidized by single electron transfer (SET) electrochemically or photochemically to generate the radical cations. For instance, enol ethers tethered redox tag serves efficient radical cation precursors for [2+2] cycloadditions.[1] The cycloadditions are net redox-neutral reactions and are initiated by the formation of a radical cation by single-electron oxidation and completed by reduction after ring formation.Herein, we present [4+2] cycloadditions using enol ethers as dienophiles by electrochemical oxidation in lithium perchlorate (LiClO4)/nitromethane (MeNO2) system. In the case of disubstituted enol ethers prepared from aldehydes, the approach involving redox tag was successful in obtaining the corresponding cycloadducts, while the desired products were not obtained when the substrates without redox tag were subjected.[2] This result suggests that intramolecular electron transfer from the redox tag is crucial for the formation of the cyclohexene ring systems. In contrast, the trisubstituted enol ethers prepared from ketones allowed the cycloaddition reaction to proceed without the involvement of redox tag. It is expected that the methyl group significantly stabilizes the cyclohexene radical cations to have enough lifetime to be reduced by intermolecular SET. Furthermore, since the cycloaddition reaction of enol ether was completed with a catalytic amount of electricity (0.4 F/mol), a radical cation chain mechanism is proposed in which electron acts as a catalyst.

Structurally diverse ent-clerodanoids from the aerial parts of Isodon scoparius

Scoparodane C (1), a diterpenoid with a rare 3,4-seco-3-nor-2,11-epoxy-ent-clerodane scaffold, was obtained from the aerial parts of Isodon scoparius, along with isocopariusines A–E (2–6), five ent-clerodanoids featuring a 5/6-fused ring system, and isocopariusines F–H (7–9), three common ent-clerodanoids. The structures of these previously undescribed compounds were established by a combination of spectroscopic analysis, X-ray diffraction, chemical derivatization, and quantum chemical calculation. Remarkably, isocopariusine B (3) showed strong resistance reversal activity against fluconazole-resistant Candida albicans.

Multi-screw extruders – an overview

Screw extrusion is a cost-effective and solvent-free method for manufacturing polymer blends and composites. This article reviews the latest developments in the field of multi-screw extruders, i.e. triple-screw, quad-screw, octa-screw, ring, planetary and multi-rotation system (MRS). The authors also discussed limitations and directions of multi-screw extruders development.

Synthesis of 3‐CF3‐Indoles from HFO‐1234ze(E) via Cross‐Coupling and Intramolecular Cyclization

AbstractThe synthesis of indoles with a trifluoromethyl group has attracted a lot of attention because they are promising structural subunits for pharmaceuticals and agrochemicals. As part of our project aimed toward the upcycling of hydrofluoroolefins (HFOs), we developed a method to construct a CF3‐bearing indole ring system through the Suzuki–Miyaura cross‐coupling of a brominated HFO‐1234ze(E) (CF3CH=CHF) with N‐tosylated o‐borylanilines, followed by nucleophilic 5‐endo‐trig cyclization at the vinylic position of the generated fluorostyrenes. We found that the Pd2(dba)3/SPhos catalyst system in the presence of K2CO3 and water in toluene afforded the corresponding 3‐CF3‐indoles in high yields in a one‐pot operation.

Dust rings trap protoplanets on eccentric orbits and get consumed by them

ABSTRACT We study the orbital evolution and mass growth of protoplanets with masses $M \in [0.1{\!-\!}8]$ M$_{{\oplus }}$ in the vicinity of a dusty ring, using three-dimensional numerical simulations with a two-fluid model and nested-meshes. We find two stable, eccentric orbits that lock the planet in the ring vicinity, thereby inhibiting its migration and allowing it to accrete dust from the ring. One of these orbits has an eccentricity comparable to the aspect ratio of the gaseous disc and has its periastron within the ring, enabling intermittent accretion during each pass. The other orbit has a smaller eccentricity and an apoastron slightly inside the ring. A planet locked at the outer orbit efficiently accretes from the ring and can reach the critical mass for runaway gas accretion on time-scales $\gtrsim 10^5$ yr (for a 10 M$_{{\oplus }}$ dust ring at 10 au), while a planet locked at the inner orbit has a slower growth and might not supersede the super-Earth stage over the disc lifetime. While in our runs a low-mass embryo forming within the ring eventually joins the outer orbit, it is likely that the path taken depends on the specific details of the ring. The trapping on the outer orbit arises from an intermittent, strong thermal force at each passage through the ring, where the accretion rate spikes. It is insensitive to uncertainties that plague models considering planets trapped on circular orbits in rings. It is highly robust and could allow a growing planet to follow an expanding ring over large distances.

The Phosphatase RosC from Streptomyces davaonensis is Used for Roseoflavin Biosynthesis and has Evolved to Largely Prevent Dephosphorylation of the Important Cofactor Riboflavin-5′-phosphate

The antibiotic roseoflavin is a riboflavin (vitamin B2) analog. One step of the roseoflavin biosynthetic pathway is catalyzed by the phosphatase RosC, which dephosphorylates 8-demethyl-8-amino-riboflavin-5′-phosphate (AFP) to 8-demethyl-8-amino-riboflavin (AF). RosC also catalyzes the potentially cell-damaging dephosphorylation of the AFP analog riboflavin-5′-phosphate also called “flavin mononucleotide” (FMN), however, with a lower efficiency. We performed X-ray structural analyses and mutagenesis studies on RosC from Streptomyces davaonensis to understand binding of the flavin substrates, the distinction between AFP and FMN and the catalytic mechanism of this enzyme. This work is the first structural analysis of an AFP phosphatase. Each monomer of the RosC dimer consists of an α/β-fold core, which is extended by three specific elongated strand-to-helix sections and a specific N-terminal helix. Altogether these segments envelope the flavin thereby forming a novel flavin-binding site. We propose that distinction between AFP and FMN is provided by substrate-induced rigidification of the four RosC specific supplementary segments mentioned above and by an interaction between the amino group at C8 of AFP and the β-carboxylate of D166. This key amino acid is involved in binding the ring system of AFP and positioning its ribitol phosphate part. Accordingly, site-specific exchanges at D166 disturbed the active site geometry of the enzyme and drastically reduced the catalytic activity. Based on the structure of the catalytic core we constructed a whole series of RosC variants but a disturbing, FMN dephosphorylating “killer enzyme”, was not generated.

Orbital dynamics in the GG Tau A system: Investigating its enigmatic disc

Context. GG Tau is one of the most studied young multiple stellar systems: GG Tau A is a hierarchical triple surrounded by a massive disc and its companion, GG Tau B, is also a binary. Despite numerous observational attempts, a comprehensive understanding of the geometry of the GG Tau A system is still elusive. Given the significant role of dynamical interactions in shaping the evolution of these systems, it is relevant to characterise the stellar orbits and the discs’ properties. Aims. To determine the best orbital configuration of the GG Tau A system and its circumtriple disc, we provide new astrometric measures of the system and we run a set of hydrodynamical simulations with two representative orbits to test how they impact a disc composed of dust and gas. Methods. We tested the dynamical evolution of the two scenarios on short and long timescales. We obtained synthetic flux emission from our simulations at different timescales and we compared them with multi-wavelength observations of 1300 µm ALMA dust continuum emission and 1.67 µm SPHERE dust scattering to infer the most likely orbital arrangement. Results. We extend the analysis of the binary orbital parameters using six new epochs from archival data, showing that the current measurements alone (and future observations coming in the next 5–10 yr) are not capable of fully breaking the degeneracy between families of coplanar and misaligned orbits, but finding that a modest misalignment is probable. We find that the timescale for the onset of the disc eccentricity growth, τecc, is a fundamental timescale for the morphology of the system. Results from the numerical simulations obtained using the representative coplanar and misaligned (∆θ = 30°) orbits show that the best match between the position of the stars, the cavity size, and the dust ring size of GG Tau A is obtained with the misaligned configuration on timescales shorter than τecc. The results exhibit an almost circular cavity and dust ring, favouring slightly misaligned (∆θ ~ 10–30°) low-eccentricity (e ~ 0.2–0.4) orbits. However, for both scenarios, the cavity size and its eccentricity quickly grow for timescales longer than τecc and the models do not reproduce the observed morphology anymore. This implies that either the age of the system is shorter than τecc or that the disc eccentricity growth is not triggered or dissipated in the system. This finding raises questions about the future evolution of the GG Tau A system and, more generally, the time evolution of eccentric binaries and their circumbinary discs.

Shoulder of Dust Rings Formed by Planet–Disk Interactions

Recent analyses of millimeter-wavelength protoplanetary disk observations have revealed several emission excesses on the previously identified dust rings, referred to as dust shoulders. The prevalence of dust shoulders suggests that they trace a common but unclear mechanism. In this work, we combine 3D, multifluid hydrodynamic simulations with radiative transfer calculations to explain the formation of dust shoulders. We find that the ring-shoulder pairs can result from the 3D planet–disk interactions with massive, gap-opening planets. The key driver is the dust filtration effect at the local pressure maximum due to planet-driven outward gas flows. Our work provides a possible explanation for the outer dust shoulders in recent super-resolution analyses of Atacama Large Millimeter/submillimeter Array observations. It also provides insights into the formation of the inner dust shoulder in the PDS 70 disk and highlights the role of 3D effects in planet–disk interaction studies.

Synthesis and Biological Activity of 2-pyridone Derivatives: A Mini Review

: The 2-pyridone nucleus is an important scaffold present in various compounds with diverse pharmacological activity. Among the reported 2-pyridone analogs, the majority of the compounds either have a substituted ring system or a fused ring system. Till now, several derivatives have been reported by different researchers for their antimicrobial activity, anticancer activity, antiviral activity, antioxidant activity, anti-hepatitis virus activity, and anti-allodynia and anti-obesity activities. In this review, we have attempted to compile synthetic methods of 2-pyridone ring by ring cyclization along with pharmacologi cal aspects related to various synthesized derivatives of the 2-pyridone nucleus.

ASASSN-21js: A multi-year transit of a ringed disc

Aims. The early-type star ASASSN-21js started to fade in 2021, as was detected by the All Sky Automated Survey for Supernovae, undergoing a multi-year eclipse that is still underway. We interpret this event as being due to a structured disc of material transiting in front of the star. The disc is in orbit around a substellar object with the mass and luminosity of a brown dwarf or smaller. We want to determine the expected duration and ending date of the eclipse. Methods. We modelled a tilted and inclined azimuthally symmetric ring system around an unseen companion and calculated the resulting time-varying light curve as the object transited in front of the star. We made an initial estimate of the ring parameters and used these as inputs to an MCMC algorithm to determine the geometric properties of the rings with associated uncertainties. Results. The model most consistent with the light curve to date is a two-ring system at high inclination with respect to the line of sight that has a semi-major axis of 71.6 stellar radii. With an estimate of the stellar radius, the transverse velocity is around 0.7 km s−1, which if bound to the star is an orbit with a semi-major axis of around 13 000 au, placing it in the Oort cloud of the parent star. The transit is ongoing and will finish around MJD 61526 (May 1 2027). We encourage the community to continue observing this object in order to understand its properties.

Computational scrutiny of psychoactive cannabinoids through molecular electrostatic potential and CB1 receptor interaction

Delta-9-THC and psychoactive derivatives were scrutinized with molecular electrostatic potential (MEP) and ligand-CB1 interaction. At the B3LYP/6-31G** level, MEP maps of the most active cannabinoids (mac), pKi ≥ 6.72 (1-13), revealed that the directional orientation of the lone pair of electrons in the phenolic OH, in general, produces a greater interaction with the substituent at position C9, orienting the carbocyclic ring system, reflecting the psychoactivity of the compounds. In addition, the existence of the side alkyl chain contributes to improving this property. In less active cannabinoids (lac), pKi < 6.72 (14-22), the negative MEP shows a more spread out, “diluted” electron density, probably due to the orientation of the carbocyclic ring system unfavorable to the pharmacophoric conformation. Furthermore, the MEP maps show cannabinoids 14-22 presenting small differences in the distribution of this density, when compared to 1-13, which seems crucial to the decrease in psychoactivity. When examining the ligand-CB1 interaction, the orientations of the compounds were shown to be governed basically by the hydrophobic pockets between helices III, IV, VI, and VII; with the most active alkyl fragment (1-13) directed to the hydrophobic site, the nonpolar fragment (methylcyclohexene) to the hydrophobic pocket, the phenolic OH to the hydrophilic pocket and the oxane fragment oriented to a small hydrophilic pocket of CB1. In the lac (14-22), the poses of the substituents COOH (14), COOCH3 (16), and COCH3 (22) were oriented towards a hydrophobic pocket and 15, 17, 18, and 21 presented the oxygenated groups directed to the hydrophilic sites of the CB1 receptor. The OH substituent in 19 directs it to the hydrophobic pocket and 20, with the OH group but distant from phenolic OH, presents said group also directed to this hydrophobic pocket of CB1. The scrutiny of cannabinoids with MEP and the ligand-CB1 interaction could guide the design of new molecules with better psychoactivity.