Navnath Gavande

Regulation of Low-Density Lipoprotein Receptor and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Expression by Zingiber officinale in the Liver of High-Fat Diet-Fed Rats

Zingiber officinale has been used to control lipid disorders and reported to possess remarkable cholesterol-lowering activity in experimental hyperlipidaemia. In the present study, the effect of a characterized and standardized extract of Zingiber officinale on the hepatic lipid levels as well as on the hepatic mRNA and protein expression of low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was investigated in a high-fat diet-fed rat model. Rats were treated with an ethanol extract of Zingiber officinale (400 mg/kg) extract along with a high-fat diet for 6 weeks. The extract of Zingiber officinale significantly decreased hepatic triglyceride and tended to decrease hepatic cholesterol levels when administered over 6 weeks to the rats fed a high-fat diet. We found that in parallel, the extract up-regulated both LDL receptor mRNA and protein level and down-regulated HMG-CoA reductase protein expression in the liver of these rats. The metabolic control of body lipid homeostasis is in part due to enhanced cholesterol biosynthesis and reduced expression of LDL receptor sites following long-term consumption of high-fat diets. The present results show restoration of transcriptional and post-transcriptional changes in low-density lipoprotein and HMG CoA reductase by Zingiber officinale administration with a high-fat diet and provide a rational explanation for the effect of ginger in the treatment of hyperlipidaemia.

2'-Methoxy-6-methylflavone: A novel anxiolytic and sedative with subtype selective activating and modulating actions at GABA A receptors

BACKGROUND AND PURPOSE Flavonoids are known to have anxiolytic and sedative effects mediated via actions on ionotropic GABA receptors. We sought to investigate this further.

Medicinal chemistry of ρ GABAC receptors

The inhibitory neurotransmitter, GABA, is a low-molecular-weight molecule that can achieve many low-energy conformations, which are recognized by GABA receptors and transporters. In this article, we assess the structure-activity relationship profiles of GABA analogs at the ionotropic ρ GABA(C) receptor. Such studies have significantly contributed to the design and development of potent and selective agonists and antagonists for this subclass of GABA receptors. With these tools in hand, the role of ρ GABA(C) receptors is slowly being realized. Of particular interest is the development of selective phosphinic acid analogs of GABA and their potential use in sleep disorders, inhibiting the development of myopia, and in improving learning and memory.

Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology

Understanding the role of GABAC receptors in the central nervous system is limited due to a lack of specific ligands. Novel γ-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane 19 were investigated to obtain selective GABAC receptor antagonists. A compound of high potency (19, K B = 10 μM) and selectivity (greater than 100 times at ρ1 GABAC receptors as compared to α1β2γ2L GABAA and GABAB(1b,2) receptors) was obtained. The cyclic phosphinic acids (17 and 19) are novel lead agents for developing into more potent and selective GABAC receptor antagonists with increased lipophilicity for future in vivo studies.

Structurally diverse GABA antagonists interact differently with open and closed conformational states of the ρ1 receptor.

Ligands acting on receptors are considered to induce a conformational change within the ligand-binding site by interacting with specific amino acids. In this study, tyrosine 102 (Y102) located in the GABA binding site of the ρ(1) subunit of the GABA(C) receptor was mutated to alanine (ρ(1Y102A)), serine (ρ(1Y102S)), and cysteine (ρ(1Y102C)) to assess the role of this amino acid in the action of 12 known and 2 novel antagonists. Of the mutated receptors, ρ(1Y102S) was constitutively active, providing an opportunity to assess the activity of antagonists on ρ(1) receptors with a proportion of receptors existing in the open conformational state compared to those existing predominantly in the closed conformational state. It was found that the majority of antagonists studied were able to inhibit the constitutive activity displayed by ρ(1Y102S), thus displaying inverse agonist activity. The exception was (±)-4-aminocyclopent-1-enecarboxamide ((±)-4-ACPAM) (8) not exhibiting any inverse agonist activity, but acting explicitly on the closed conformational state of ρ(1) receptors (ρ(1) wild-type, ρ(1Y102C) and ρ(1Y102A)). It was also found that the GABA antagonists were more potent at the closed compared to the open conformational states of ρ(1) receptors, suggesting that they may act by stabilizing closed conformational state and thus reducing activation by agonists. Furthermore, of the antagonists tested, Y102 was found to have the greatest influence on the antagonist activity of gabazine (SR-95531 (13)) and its analogue (SR-95813 (14)). This study contributes to our understanding of the mechanism of inverse agonism. This is important, as such agents are emerging as potential therapeutics.

Identification of Benzopyran‐4‐one Derivatives (Isoflavones) as Positive Modulators of GABAA Receptors

g-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the mammalian central nervous system (CNS), with 25–50 % of synapses being GABA-ergic in nature. GABA influences neurons via three major classes of receptors, which are grouped on the basis of their subunit composition, gating properties, and pharmacological profiles, and termed GABAA, GABAB, and GABAC (GABA 1) receptors. GABAA and GABAC receptors are ligand-gated chloride ion channels, whereas GABAB receptors are G protein-coupled receptors. [2] The ionotropic GABAA receptors are transmembrane protein complexes composed of five heteropentameric subunits. To date, 16 human GABAA receptor subunits have been identified, and they have been classified into a (a1–a6), b (b1–b3), g (g1– g3), d, e, p, and q. Although a wide range of different GABAA receptor combinations exists in vivo, the a1b2g2 subunit combination represents the most dominant receptor subtype in the human brain. 3] Enhancement of chloride ion flux at GABAA receptors by positive modulators is one of the most powerful therapeutic strategies for the treatment of CNS-related disorders, such as generalized anxiety, panic disorders, sleep disturbances, muscle spasms and seizure disorders. 4] Positive modulators of GABAA receptors, such as benzodiazepines, neuroactive steroids, barbiturates, and loreclezole, have been identified as useful for the treatment of CNS-related disorders. Benzodiazepines are commonly prescribed drugs, but they produce a range of both desirable and unwanted side effects, such as sedation, myorelaxation, rebound anxiety, dependence, tolerance, strong interactions with alcohol, and amnesia. 5] However, based on recent advances in GABAA receptor pharmacology, subtype-selective agents and modulators that bind to the GABAA receptor at sites other than the classical benzodiazepine binding site may offer an opportunity to discover novel therapeutic agents with fewer adverse side effects. 6] Thus, the identification of novel templates for positive modulation of GABAA receptors represent an important objective in drug discovery for the treatment of CNS-related disorders. Using functional electrophysiological studies on recombinant receptors, we and others recently revealed that flavonoids (flavones/flavanones/flavan-3-ols) are able to interact with binding sites on the GABAA receptor that are independent of the classical high-affinity, flumazenil-sensitive, benzodiazepine binding site. In contrast, many previous studies demonstrated that a range of naturally occurring and synthetic flavonoids displace radiolabelled benzodiazepines in rat brain tissue binding to the high-affinity benzodiazepine binding site with nanomolar affinity. Thus, the benzopyran-4-one (flavonoid) pharmacophore is emerging as a potential template for the treatment of CNS-related disorders, although the exact mechanism and location of the binding site have not yet been elucidated. Isoflavones are a subgroup of flavonoids, which differ from flavones in location of the substituted phenyl group (Figure 1). Isoflavones are natural antioxidants and have diverse effects

Design, Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ρ1 GABAC Receptors.

The ρ1 GABAC receptor is a ligand-gated chloride ion channel that shows promise as a therapeutic target for myopia, sleep disorders, memory and learning facilitation, and anxiety-related disorders. As such, there is a need for molecular probes to understand the role GABAC receptors play in physiological and pathological processes. To date, no labeled (either radioactive or fluorescent) GABAC selective ligand has been developed that can act as a marker for GABAC receptor visualization and localization studies. Herein, we report a series of fluorescent ligands containing different-sized linkers and fluorophores based around (S)-4-ACPBPA [(4-aminocyclopenten-1-yl)-butylphosphinic acid], a selective GABAC antagonist. One of these conjugates, (S)-4-ACPBPA-C5-BODIPY (13), displayed moderate potency (IC50 = 58.61 μM) and selectivity (>100 times) for ρ1 over α1β2γ2L GABAA receptors. These conjugates are novel lead agents for the development of more potent and selective fluorescent probes for studying the localization and function of GABAC receptors in living cells.