Structure–activity relationships of 44 halogenated compounds for iodotyrosine deiodinase-inhibitory activity

The aim of this study was to investigate the possible influence of halogenated compounds on thyroid hormone metabolism via inhibition of iodotyrosine deiodinase (IYD) activity. The structure-activity relationships of 44 halogenated compounds for IYD-inhibitory activity were examined in vitro using microsomes of HEK-293 T cells expressing recombinant human IYD. The compounds examined were 17 polychlorinated biphenyls (PCBs), 15 polybrominated diphenyl ethers (PBDEs), two agrichemicals, five antiparasitics, two pharmaceuticals and three food colorants. Among them, 25 halogenated phenolic compounds inhibited IYD activity at the concentration of 1 × 10^?4 M or 6 × 10^?4 M. Rose bengal was the most potent inhibitor, followed by erythrosine B, phloxine B, benzbromarone, 4′-hydroxy-2,2′,4-tribromodiphenyl ether, 4-hydroxy-2,3′,3,4′-tetrabromodiphenyl ether, 4-hydroxy-2′,3,4′,5,6′-pentachlorobiphenyl, 4′-hydroxy-2,2′,4,5′-tetrabromodiphenyl ether, triclosan, and 4-hydroxy-2,2′,3,4′,5-pentabromodiphenyl ether. However, among PCBs and PBDEs without a hydroxyl group, including their methoxylated metabolites, none inhibited IYD activity. These results suggest that halogenated compounds may disturb thyroid hormone homeostasis via inhibition of IYD, and that the structural requirements for IYD-inhibitory activity include halogen atom and hydroxyl group substitution on a phenyl ring.     

Synthesis and leishmanicidal activity of cinnamic acid esters: structure–activity relationship

Several cinnamic acid esters were obtained via Fischer esterification of cinnamic acids derivatives with aliphatic alcohols. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against L. (V) panamensis amastigotes and cytotoxic activity was evaluated against mammalian U-937 cells. The compounds 11, 15–17, and 23, were active against Leishmania parasite and although toxic for mammalian cells, they still are potential candidates for antileishmanial drug development. A SAR analysis indicates that first, while smaller alkyl chains lead to higher selectivity indices (10, 11 vs. 12–17); second, the degree of oxygenation is essential for activity, primarily in positions 3 and 4 (17 vs. 18–20 and 22); and third, hydroxyl groups increase both activity and cytotoxicity (14 vs. 23). On the other hand, the presence of a double bond in the side chain is crucial for cytotoxicity and leishmanicidal activity (12 vs. 21). However, further studies are required to optimize the structure of the promising molecules and to validate the in vitro activity against Leishmania demonstrated here with in vivo studies.     

Does furosemide have vasodilator activity?

Furosemide decreases peripheral resistance in hypertensive patients and dilates veins in patients with congestive heart failure. There is evidence that both these actions are due to an effect on blood vessel tone which requires the presence of the kidneys but is not a result of a diuretic-induced loss of volume. John Gerkens presents experimental evidence which supports his proposal that furosemide may release a hormone from the kidney, possibly from the renal papilla, which leads to an inhibition of vasoconstriction. This inhibition requires an intact endothelium in the blood vessel.     

Synthesis and antiproliferative activity of substituted diazaspiro hydantoins: a structure–activity relationship study

Summary  In the course of structure–activity relationship studies and to explore the antiproliferative effect associated with the hydantoin framework, diversely substituted several diazaspiro hydantoins were synthesized. Variation in the functional group at N-terminal of the hydantoin ring and coupling of different substituted aromatic acids in 4-aminocyclohexanone ring led to three sets of compounds. The antiproliferative effect of the compounds was evaluated in vitro using the MTT colorimetric method against one normal cell line (NDF-103 skin fibroblast cells) and four human cancer cell lines (MCF-7 breast carcinoma cell line, HepG-2 hepatocellular carcinoma cell line, HeLa cervix carcinoma cell line and HT-29 colon carcinoma cell line) for the time period of 24 h. Among the series, some compounds exhibited interesting growth inhibitory effects against all four cell lines. From the SAR studies, it reveals that, the substitution at N-terminal in hydantoin ring plays key role in the antiproliferative activity.     

PFC control VTA DA neurons activity

Aim： To investigate the functional correlation between medial prefrontal cortex （mPFC） and ventral tegmental area （VTA）. Methods ： VTA DA neurons firing and PFC local field potential （LFPs） were simultaneously recorded with multisites recording in chloral hydrate - anesthetized rats. Results： Based on the relative amplitude of the slow oscillation （ SO）, we divided VTA DA neurons into two groups ： high SO （HS） and low SO （LS）. Nearly half of 232 （47%） VTA DA neurons were HS cells because the mean power between 0. 5 - 1.5Hz （P0. 5-1. 5Hz ） in their autospectra was significantly higher than that between 0 -3Hz （P0-3Hz）. In most VTA DA cells （67%）, the SO was significantly coherent with mPFC LFPs with a high coherence. We refer to these DA neurons as PFC - coupled （PC） cells, which included both high SO （HS） and low SO （LS） cells, mPFC inactivation induced by TTX local infusion significantly decreased the SO in most cells tested （27/29）, and had no significant effect on firing rate and bursting. Compared to non - lesioned rats, mPFC transection markedly decreased both the number of HS cells and the amplitude of the SO. Phase analysis between VTA DA neuron firing and mPFC LFPs suggests that the SO in most DA neurons has a nearly anti - phase relation with PFC oscilla- tions and the phase lag between the SO and PFC was greater than 40% of a cycle period. In most PFC pyramidal neurons,     

β2-Adrenoceptor agonist activity of higenamine

Higenamine was included in the World Anti-Doping Agency (WADA) Prohibited Substances and Methods List as a β₂-adrenoceptor agonist in 2017, thereby resulting in its prohibition both in and out of competition. The present mini review describes the physiology and pharmacology of adrenoceptors, summarizes the literature addressing the mechanism of action of higenamine and extends these findings with previously unpublished in silico and in vitro work. Studies conducted in isolated in vitro systems, whole-animal preparations and a small number of clinical studies suggest that higenamine acts in part as a β₂-adrenoceptor agonist. In silico predictive tools indicated that higenamine and possibly a metabolite have a high probability of interacting with the β₂-receptor as an agonist. Stable expression of human β₂-receptors in Chinese hamster ovary (CHO) cells to measure agonist activity not only confirmed the activity of higenamine at β₂ but also closely agreed with the in silico prediction of potency for this compound. These data confirm and extend literature findings supporting the inclusion of higenamine in the Prohibited List.     

2,3-Dibenzylbutyrolactones and 1,2,3,4-tetrahydro-2-naphthoic acid γnes: structure and activity relationship in cytotoxic activity

Dibenzyl-g-butyrolactone and 1,2,3,4-tetrahydro-2-naphthoic acid gamma-lactone (TNL) derivatives were synthesized and evaluated for cytotoxic activity against some cancer cell lines. It was found that TNL derivatives with a shorter distance between C-4 in ring A and C'-2 in ring C were more cytotoxic, while dibenzyl-gamma-butyrolactones with a longer one were nearly inactive. In TNL series, presence of 3,4-dioxy group in ring A and 2-methoxy group in ring C was essential for the enhancement of the activity.     

Aminothiazolomorphinans with mixed κ and μ opioid activity

A series of N-substituted and N'-substituted aminothiazole-derived morphinans (5) were synthesized for expanding the structure-activity relationships of aminothiazolo-morphinans. Although their affinities were somewhat lower than their prototype aminothiazolo-N-cyclopropylmorphinan (3), 3-aminothiazole derivatives of cyclorphan (1) containing a primary amino group displayed high affinity and selectivity at the κ and μ opioid receptors. [(35)S]GTPγS binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid receptor. These novel N'-monosubstituted aminothiazole-derived morphinans may be valuable for the development of drug abuse medications.     

Intrinsic sympathomimetic activity ofβ-adrenoceptor blocking agents

Summary The pharmacological methods used to assess the intrinsic sympathomimetic activity (ISA) of -blockers are discussed. The clinical relevance of ISA to respiratory function, peripheral resistance and cardiac function is reviewed. It appears doubtful whether ISA is always of predominant clinical significance and an alternative explanation is offered for many clinical effects observed with certain -blockers, e.g. pindolol, oxprenolol, tolamolol, metoprolol, etc. Some effects of these -blockers resemble those of labetalol, a new drug with both - and -blocking activity. Some clinical effects of certain -blockers are more likely to be due to -blocking activity than to their ISA.     

Structure–activity relationships for α-calcitonin gene-related peptide

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin (CT) family of peptides. It is a widely distributed neuropeptide implicated in conditions such as neurogenic inflammation. With other members of the CT family, it shares an N-terminal disulphide-bonded ring which is essential for biological activity, an area of potential α-helix, and a C-terminal amide. CGRP binds to the calcitonin receptor-like receptor (CLR) in complex with receptor activity-modifying protein 1 (RAMP1), a member of the family B (or secretin-like) GPCRs. It can also activate other CLR or calcitonin-receptor/RAMP complexes. This 37 amino acid peptide comprises the N-terminal ring that is required for receptor activation (residues 1–7); an α-helix (residues 8–18), a region incorporating a β-bend (residues 19–26) and the C-terminal portion (residues 27–37), that is characterized by bends between residues 28–30 and 33–34. A few residues have been identified that seem to make major contributions to receptor binding and activation, with a larger number contributing either to minor interactions (which collectively may be significant), or to maintaining the conformation of the bound peptide. It is not clear if CGRP follows the pattern of other family B GPCRs in binding largely as an α-helix.

LINKED ARTICLES

This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7     

Inhibitory potential of traditional herbs on α-amylase activity

Context: There has been enormous interest in the development of alternative medicines for the control of diabetes. Use of carbohydrate-hydrolyzing enzyme inhibitors proved to be an important strategy for the management of postprandial hyperglycemia by delaying the process of carbohydrate hydrolysis and absorption.

Objective: Three common traditional herbs, namely, stem bark of Terminalia arjuna (Combretaceae), seeds of Eugenia cumini (Myrtaceae), and leaves of Aegle marmelos (Rutaceae), were tested for their α-amylase inhibitory activities to establish antidiabetic potential.

Materials and methods: The plant extracts (aqueous, 50%, and 100% methanol) obtained were subjected to an in vitro amylase inhibitory assay using starch as a substrate and pancreatic amylase as the enzyme. Statistical differences and linear regression analysis were performed using GraphPad prism 5 software.

Results: The 50% methanol extracts of T. arjuna, E. cumini, and A. marmelos at a concentrations 50–500 μg/mL showed maximum percentage inhibition on amylase activity with IC₅₀ values of 302?±?0.55, 632?±?0.21, and 503?±?0.28 μg/mL, respectively. However, the 100% methanol extracts of all the three plants showed the least inhibitory activity.

Discussion and conclusion: The results show that T. arjuna > E. cumini > A. marmelos have excellent inhibitory activity and, therefore, might be effective in lowering postprandial hyperglycemia.     

Biophysical activity of pulmonary surfactant：an alternative view

Pulmonary surfactant has long been recognized as a potential factor in the development and perpetuation of the acute respiratory distress syndrome(ARDS). Attempts to use therapeutic surfactants in the treatment of ARDS, however, have been frustrated by the lack of agents that are both biophysically active and available in     

Insecticidal activity and structure–activity relationship of sugar embedded macrocycles for the control of aphid (Aphis craccivora Koch)

Abstract

Toxicity of sugar embedded macrocycles was evaluated for their toxicity against nymphs of aphid, Aphis craccivora Koch (Hemiptera: Aphididae) in the laboratory conditions. Most of the compounds showed toxicity to A. craccivora. However, the activity of different macrocycles varied depending on the nature and position of various functional groups possess by these compounds. Results revealed that among them, compound 3c found more effective for the control of A. craccivora (LC₅₀?=?413?mg?L^–1) and was followed by 3b (LC₅₀?=?442.62?mg?L^?1) and 3e (LC₅₀?=?480.19?mg?L^?1).     

Hypolipidemic activity of d-pantothenic acid 4′-phosphate salts

Translated from Khimikofarmatsevticheskii Zhurnal, Vol. 24, No. 8, pp. 31–34, August, 1990.     

Antiviral activity of ammonium salts of β-alkylthiopropionic acids

A number of ammonium salts of -alkylthiopropionic acids and their oxidized derivatives, as well as two oxygen analogs and phenyl hydroxide, were synthesized and their antiviral activity was studied. Derivatives with a smaller alkyl radical (C₂-C₃) were found to have a higher antiviral activity. The results suggest that -alkylthiopropionic acid derivatives may be promising in the search for antiviral preparations.