The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.

Evaluation of Herbal Extract of Gentiana diffusa for Antianxiety Activity

The present study was designed to authenticate the anti-anxiety activity (by using elevated plus maze model) of methanolic extract of the leaves of Gentiana diffusa. by authors Swiss Albino mice were treated with different doses of the leaf extracts (200 mg / kg p.o.) and Diazepam (2mg/ kg, p.o) was used as a positive control. Results of study show that methanolic extract in higher doses (200 mg/kg) possesses marked anti-anxiety activity and was comparable to the effect produced by diazepam. The plant can be developed as a commercial source of anxiolytic agent. Further studies are in process to isolate the active constituent responsible for this activity and mechanism of action. Keywords: Leaves, Methanol, Anxiety, Diazepam

Identification of Anxiolytic Potential of Niranthin: In-vivo and Computational Investigations

Anxiety is an unpleasant state, which can critically decrease the quality of life is often accompanied by nervous behaviour and rumination. Niranthin is a lignan isolated from various Phyllanthus sources. The literature survey on niranthin highlights wide ranges of the therapeutic potentials. In a present study, based on our previous investigations, we evaluated pure, isolated and characterized niranthin as an anxiolytic agent. The niranthin [6-[(2R,3R)-3-[(3,4-dimethoxyphenyl)methyl]-4-methoxy-2-(methoxymethyl)butyl]-4-methoxy-1,3-benzodioxole] was purchased from commercial source and further subjected for assessment of its anxiolytic potentials using popular animal models including Elevated plus-maze model/test (EPM) and Light & Dark Exploration test (L&D). GABA-A receptor mediation was evaluated by pretreating the mice with the GABA-A receptor antagonist Flumazenil before the EPM task. Molecular docking simulation studies (pdb id: 4COF) carried out by Vlife QSAR software showed that niranthin (docking score: − 62.1714 kcal/mol) have shown comparatively best docking score compared to the standard drug Diazepam (docking score: − 63.1568 kcal/mol). To conclude, Niranthin has probable potential in the management of anxiety disorder. Our in-silico and in-vivo analysis (indirectly) indicated the plausible role of GABA mediation for anxiolytic activity. Although, these studies are preliminary, future in depth experimental explorations will be required to use Niranthin as anti-anxiety drug in near future. Graphic Abstract

Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of Haemonchus contortus In Vitro

Kava extract, an aqueous rhizome emulsion of the plant Piper methysticum, has been used for centuries by Pacific Islanders as a ceremonial beverage, and has been sold as an anxiolytic agent for some decades. Kavalactones are a major constituent of kava extract. In a previous investigation, we had identified three kavalactones that inhibit larval development of Haemonchus contortus in an in vitro-bioassay. In the present study, we synthesized two kavalactones, desmethoxyyangonin and yangonin, as well as 17 analogues thereof, and evaluated their anthelmintic activities using the same bioassay as employed previously. Structure activity relationship (SAR) studies showed that a 4-substituent on the pendant aryl ring was required for activity. In particular, compounds with 4-trifluoromethoxy, 4-difluoromethoxy, 4-phenoxy, and 4-N-morpholine substitutions had anthelmintic activities (IC50 values in the range of 1.9 to 8.9 µM) that were greater than either of the parent natural products—desmethoxyyangonin (IC50 of 37.1 µM) and yangonin (IC50 of 15.0 µM). The synthesized analogues did not exhibit toxicity on HepG2 human hepatoma cells in vitro at concentrations of up to 40 µM. These findings confirm the previously-identified kavalactone scaffold as a promising chemotype for new anthelmintics and provide a basis for a detailed SAR investigation focused on developing a novel anthelmintic agent.

Psychedelic Properties of Peganum Harmala: Macrodose and Microdose Reports

Peganum harmala has been used for millennia in traditional medicine and religious rites. Recent phytopharmaceutical research has given credence to its traditional uses, demonstrating a wide range of potential therapeutic uses, including its use as antidepressant and anxiolytic agent. Entheogenic at high doses, P. harmala can create profound psychedelic experiences with lasting positive effects that echo those seen in research on other psychedelics. Anecdotal evidence from online forums suggests P. harmala may be able to provide results similar to microdosing other psychedelics, though no research exists on this potential. This paper presents the first evidence of P. harmala’s effects when used in a daily microdosing protocol. KEY WORDS Peganum harmala, Syrian rue, macrodose, microdose, EEG, psychedelic, entheogen, affect, burnout, extraction.

Anxiolytic effects of the flavonoid luteolin in a mouse model of acute colitis

Anxiety related disorders commonly occur in association with major depressive disorder (MDD) in individuals suffering from peripheral inflammation, with a higher prevalence among IBS patients. We have previously shown that the bioflavonoid luteolin has pronounced analgesic and antidepressant-like effects in mice with dextran sodium sulfate (DSS)-induced colitis. Here, we further evaluate the biological effect of luteolin as a possible anxiolytic agent in DSS treated mice. Anxiolytic action was evaluated using the open field test (OF), the novelty suppressed feeding test (NSFT) and the elevated plus maze test (EPM). Luteolin increased the number of crossings in the center of the OF apparatus, reduced the latency to interact with the food pellet in the NSFT, and increased the time spent in the open arms in the EPM. These results suggest luteolin as a possible natural anxiolytic molecule without sedative effects, thus reinforcing its therapeutic potential for the comorbidities involving peripheral inflammation, pain, mood and anxiety-related disorders.

Evaluation of anxiolytic properties of BacoMind extract of plant Bacopa monnieri Linn. in comparison with diazepam in rodent model

Background: Anxiety is a state characterized by somatic, emotional, cognitive, and behavioral components, associated with significant disability. The pharmacotherapy for anxiety remains limited for achievable safety and tolerability of the medicines. Benzodiazepines use associated with side effects like psychomotor impairment and addiction liability. Due to the ADRs associated with antianxiety drugs, the drug trials have focused on screening herbal medicines that are reportedly used in the treatment of anxiety and which have minimal side effects.Methods: The anxiolytic activity was examined by using the elevated plus maze (EPM) and open field test (OFT), forty Albino wistar strain rats of both sex of weighing 120 to 200 g were divided into four groups of ten rats each.. Group 1 received vehicle (normal saline); group 2 received diazepam (1 mg/kg); groups 3 and 4 received BacoMind™, 30 and 60 mg/kg oral, respectively.Results: Rats treated with diazepam (1 mg/kg, p.o.) showed significant (p<0.001) increase in the percentage of open arms entries and time spent whereas, in closed arm the number of entries and time spent were significantly (p<0.05) decreased. Intraperitonial administration of BacoMind™ extract of plant Bacopa monnieri Linn. exhibited significant (p<0.05) increase in the number of open arm entries and time spent with significant (p<0.05) reduction in number of entries and time spent in the closed arm as compared to group 1. BacoMind™ treated rats also produced significant increase in the number of rearings (p<0.05), assisted rearings and number of squares crossed (p<0.01).Conclusions: BacoMind™ extract of plant Bacopa monnieri Linn possess significant anxiolytic activity in the rats. It can be a promising anxiolytic agent.

Development and Validation of a High-Performance Thin-Layer Chromatographic (HPTLC) Method for Simultaneous Quantification of Reserpine, Atropine, and Piperine in Sarpagandha Ghanvati, a Classical Ayurvedic Preparation

Background: Anxiety disorders are the most common of emotional disorders, affecting more than 20 million people annually. Sarpagandha Ghanvati is a classical Ayurvedic polyherbal formulation prescribed in conditions of insomnia, hysteria, and is used as an anxiolytic agent. Standardization and quality control are the two major issues that need to be addressed for herbal formulations, especially those containing multiple herbal ingredients. Objective: An HPTLC method was developed for the simultaneous quantification of reserpine, atropine, and piperine from Sarpagandha Ghanvati containing Rauwolfia serpentine (root), Hyoscyamus niger (seed), and Piper longum (root and stem). Methods: The marker compounds were effectively resolved on a silica gel G TLC plate using toluene–ethyl acetate–diethyl amine (7+2+1, v/v) as the mobile phase. The detected wavelengths for reserpine, atropine, and piperine were 269, 220, and 254 nm, respectively. The method was validated as per the International Conference on Harmonization guidelines. Results: R. serpentine roots contained 0.82% w/w of reserpine. Atropine content in the seeds of H. niger was found to be 0.004% w/w, whereas P. longum roots were found to contain 0.508% of piperine. The method was found to be accurate, which was evident from 98.93, 99.46, and 99.10% recovery of reserpine, atropine, and piperine, respectively, when the respective herbs were spiked with them. By the developed HPTLC method, 1.0 g of Sarpagandha Ghanvati was found to contain 4.94, 0.049, and 0.318 mg of reserpine, atropine, and piperine, respectively. The recoveries of these three markers from the formulation were found to be 90.32, 92.45, and 89.97%, respectively. Conclusions: The developed method can be successfully used for simultaneous estimation of these marker compounds and for the quality control of the classical Ayurvedic formulation Sarpagandha Ghanvati. Highlights: This works describes effects of extraction solvents on the quantities of marker compounds in the formulations. It also suggests a simple and reliable HPTLC method for simultaneous quantification of three different marker compounds from a poly-herbal formulation.