A conceptual framework of urban food security and nutrition in low- and middle-income country settings applied to the Asia-Pacific region.

A conceptual framework is presented for enhancing food security and nutrition in urban areas in low- and middle-income countries, highlighting key influencing factors, including food supply chains, community food environments, community infrastructure and services, and numerous underlying individual and household determinants, such as behaviours and dietary practices.

Implications of US agricultural data practices for sustainable food systems research.

Using the tenets of data feminism, we analyse the National Agricultural Statistics Service Quick Stats database - the primary repository of United States agricultural data. We identify unstated assumptions built into the database's scaffolding through data collection, aggregation and dissemination practices, revealing how they facilitate granular analyses of agricultural topics historically judged as national priorities while leaving unilluminated many others of vital importance for contemporary sustainability needs. We argue that this entrenches an inequitable and unsustainable food systems status quo, and we offer recommendations for data providers and users based on principles of reflexivity, context and pluralism.

Design, development, and local production of lipid-based nutritional supplements to enhance the complementary feeding diet: A model for collaboration for a feeding trial in Bangladesh.

Background: Lipid-based nutrient supplements (LNS) are effective for treating childhood wasting and for preventing stunting, wasting, and anemia, but large-scale production and programmatic use are a barrier. Locally-developed and produced LNS may be more affordable and reduce logistical procurement and importation hurdles, while promoting private sector engagement and partnership. Methods: In northwestern Bangladesh, we conducted a community-based trial of complementary food supplementation to test its efficacy to reduce childhood stunting. Two locally-developed, small-quantity LNS (20g/day, rice-lentil and chick-pea based) were designed, developed first at small scale in the 'kitchen' laboratory under controlled conditions, followed by taking them to a local food manufacturer for larger production for the study. We describe here the partnership, required expertise and capacity, experiences, and lessons learned that made this uniquely complex undertaking possible Results: Key steps in the journey included addressing the dynamics of clear communication between partners, executing on carefully assigned tasks and roles, correcting course when needed, and maintaining timeliness and roadmaps. Knowledge of food science and technology was key in solving many food-production challenges that were encountered in taking the laboratory recipe to the factory. Factory production was established and had to meet quality and hygiene criteria set for young children. Conclusions: We provide documentation of this experience as a model to describe the various steps and considerations and what is entailed in local LNS production. We highlight the importance of a well-conceived collaboration with clear roles that created a 'win-win' situation for all partners for achieving common goals, establishing improved technology at the factory, and building new capacity to produce such products for children in a low resource setting. Key words: micronutrient, lipid-based nutrient supplements, maternal and child, malnutrition, multiagency collaboration.

Water in the West: Trends, production efficiency, and a call for open data.

Climate change is projected to transform US agriculture, particularly in places reliant on limited irrigation water resources. As water demand and scarcity increase simultaneously over the coming decades, water managers and growers will need to optimize water use on their irrigated lands. Understanding how growers maintain high yields in arid, water stressed places, while conserving water, is of key importance for the future of US agriculture in the West. We explore water use management and trends in irrigated agriculture in the Western US using operator-level USDA-NASS Farm and Ranch Irrigation Survey/Irrigation and Water Management Survey data aggregated for the first time to the county-scale. In this exploration, we build the first county-level, openly accessible dataset linking farm(er) characteristics to irrigation behaviors in the West. We find notable spatial and temporal variability in Western irrigation practices, with neighboring counties exhibiting large differences in efficiency, water use, and crop yields, as well as in the sources of information, scheduling methods, and technological improvements employed. To produce effective management initiatives in the West, we call for the express and open dissemination of USDA irrigation data at sub-state scales. These data will contribute to our understanding of irrigated production and could support a pathway that will prepare growers for a more resilient agricultural future.

Phenylethyl-substituted pyrimido[2,1-f]purinediones and related compounds: structure-activity relationships as adenosine A(1) and A(2A) receptor ligands.

The synthesis of N-(un)substituted-phenylalkylpyrimido[2,1-f]purinediones was performed starting with 7-(3-chloropropyl)-8-bromotheophylline and 7-(3-chloropropyl)-8-bromo-1,3-dipropylxanthine. Compounds with unsubstituted or substituted ethylene spacer to an aromatic ring were synthesized. Additionally variations in the spacer-elongation of the linker containing more than two atoms, introduction of a double bond or heteroatoms were performed. Physicochemical properties of the synthesized compounds were described. The obtained compounds envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A(1) and A(2A) receptors, the receptor subtypes that are predominant in the brain. Selected compounds were also investigated for the affinity to the A(2B) and A(3) receptor subtypes. It was stated that phenylethyl pyrimido[2,1-f]purinediones and their analogs with variations of the ethylene spacer (substituted or extended) exhibit micromolar or submicromolar affinity for A(2A) ARs (adenosine receptors); for example compound 2Ac with p-hydroxy substituent displayed a K(i) value of 0.23 microM at the rat A(2A) receptor. In comparison to the previously obtained phenyl and benzyl pyrimido[2,1-f]purinediones compounds with a shorter spacer, phenethyl derivatives were optimal for A(2A) AR. The kind of substituent at the aromatic ring was important for the affinity. Oxygen and nitrogen atoms in the spacer resulted frequently in a slight decrease of the A(2A) AR affinity, introduction of more heteroatoms into the spacer-in carbamates-caused distinctly negative effect on the activity. In this series of compounds more frequently the adenosine A(1) activity was observed, also in submicromolar range as for dipropyl derivative 2Ba with K(i) value of 0.62 microM at the rat A(2A) AR. 3D-QSAR models were developed for the compounds presented in this paper as well as in the previous publications showing activity at adenosine A(1) and A(2A) ARs. It was concluded that for the activity at adenosine A(1) and A(2A) receptors lipophilicity, steric effects along with the molecule's electrostatic surface properties had greatest value. Chosen compounds were evaluated in vivo as anticonvulsants in MES, scMet tests and examined for neurotoxicity. Contrary to previously obtained phenyl and benzyl pyrimido[2,1-f]purinediones, all tested compounds were inactive as anticonvulsants.

N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors.

Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either. The obtained compounds (1-20) were evaluated for their affinity to adenosine A1 and A2A receptors, selected compounds were additionally investigated for affinity to the A3 receptor subtype. The results of the radioligand binding assays to A1 and A2A adenosine receptors showed that most of the 1,3-dimethyl-9-benzylpyrimidopurinediones exhibited selective affinity to A2A receptors at micromolar or submicromolar concentrations (for example, derivative 9 with o-methoxy substituent displayed a Ki value of 0.699 microM at rat A2A receptor with more than 36-fold selectivity). Contrary to previously described arylpyrimido[2,1-f]purinediones dipropyl derivatives (compounds 15-20) showed affinity to both kinds of receptors increased, however A1 affinity increased to a larger extent, with the result that A2A selectivity was abolished. The best adenosine A1 receptor ligand was m-chlorobenzyl derivative 18 (Ki=0.089 microM and 5-fold A1 selectivity). Structure-activity relationships were discussed with the analysis of lipophilic and spatial properties of the investigated compounds. Pharmacophore model of adenosine A1 receptor antagonist was adopted for this purpose.

Improving potency, selectivity, and water solubility of adenosine A1 receptor antagonists: xanthines modified at position 3 and related pyrimido[1,2,3-cd]purinediones.

The structure-activity relationships of xanthine derivatives related to the adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 1,3-dipropyl-8-(3-noradamantyl)xanthine (KW3902) were investigated by focusing on variations of the 3-substituent. Aromatic residues were well tolerated by the A(1) receptor in that position. A moderate effect of stereochemistry was found for the 3-(1-phenylethyl)-substituted analogue of DPCPX (S>R) at A(1) and A(3) receptors, whereas the opposite stereoselectivity was observed at the A(2) receptor subtypes. A 3-hydroxypropyl substituent was found to be optimal for high A(1) affinity and selectivity. The most potent compound of the present series was 1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine (10 c), which exhibits a K(i) value of 0.124 nM at rat, and 0.7 nM at human adenosine A(1) receptors, combined with high selectivity (>>200-fold) versus the other receptor subtypes. The similarly potent 8-cyclopentyl-3-(3-hydroxypropyl)-1-propylxanthine was converted into a water-soluble phosphate prodrug, which may become a useful pharmacological tool for in vivo studies. 8-Alkyl-2-(3-noradamantyl)pyrimido[1,2,3-cd]purine-8,10-diones, which can be envisaged as xanthine analogues with a fixed 3-propyl substituent, were identified as a new class of potent, selective adenosine A(1) receptor antagonists. For example, compound 14 (8-butyl-substituted) exhibits a K(i) value of 13.8 nM at human A(1) receptors. A selection of the most potent compounds was investigated in [(35)S]GTPgammaS binding assays and showed inverse agonistic activity. Their efficacy was generally lower than that of the full inverse agonist DPCPX, and depended on subtle structural changes. Some of the new compounds belong to the most potent and selective A(1) antagonists described to date.

Synthesis and biological activity of tricyclic aryloimidazo-, pyrimido-, and diazepinopurinediones.

Syntheses and physicochemical properties of N-aryl-substituted imidazo-, pyrimido-, and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-haloalkyl-8-bromo-1,3-dimethyl- or 1,3-dipropyl-xanthine derivatives with corresponding arylamines. The obtained compounds (1-40), which can be envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A(1) and A(2A) receptors, the receptor subtypes that are predominant in the brain. Selected compounds were additionally investigated for affinity to the A(2B) and A(3) receptor subtypes. Many of the compounds showed adenosine A(2A) receptor affinity at micromolar or submicromolar concentrations and were A(2A)-selective, for example, compound 23 with p-fluoro substituent displayed K(i) value of 0.147 microM at the rat A(2A) receptor and more than 170-fold-A(2A) selectivity, compound 17 with naphthyl substituent had K(i) value of 0.219 microM and a more than 114-fold-A(2A) selectivity. The compounds were somewhat weaker and less selective at the human receptor subtypes. Elongation of the dimethyl substituent to dipropyl in xanthine moiety improved affinity but reduced selectivity. 1,3-Dimethylimidazo-, pyrimido-, and diazepinopurinediones were evaluated in vivo as anticonvulsants in MES, ScMet, TTE tests and examined for neurotoxicity in mice (ip). Substances with pyrimido ring displayed protective activity in ScMet or in MES and ScMet tests, showing also neurotoxicity. The pyrimidine annelated ring is beneficial for both receptor affinity and anticonvulsant activity.

Tricyclic oxazolo[2,3-f]purinediones: potency as adenosine receptor ligands and anticonvulsants.

Synthesis and physicochemical properties of 7-mono- and 6,7-disubstituted dihydrooxazolo-[3,2-f]purinediones are described. Oxazolo[2,3-f]purinediones were synthesized by cyclization of 8-bromotheophylline with oxiranes. The obtained compounds (1-22) were evaluated for their affinity at adenosine A(1) and A(2A) receptors. They showed mainly adenosine A(2A) receptor affinity at low micromolar concentrations and A(2A) selectivity, for example, compound 9 with an octyl substituent at the oxazole ring displayed adenosine A(2A) receptor affinity (K(i)=0.998 microM) and at least 25-fold A(2A) versus A(1) selectivity. This compound was less selective (5-fold) towards human recombinant A(2B) and A(3) adenosine receptors. In this group of compounds active adenosine A(1) receptor antagonists were also identified. Oxazolopurinediones were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (ip). Compounds with long alkyl chains showed anticonvulsant activity in both tests (in 100 and 300 mg/kg doses), accompanied by significant neurotoxicity. The anticonvulsant activity in rats (po) was higher and without signs of neurotoxicity. SAR and QSAR studies stressed the importance of lipophilic 7-substituents for both types of pharmacological activity. The volume of the substituent is, however, limited at the A(2A) AR, an n-octyl group being optimal.

Imidazo[2,1-b]thiazepines: synthesis, structure and evaluation of benzodiazepine receptor binding.

As a continuation of our search for new ligands acting on benzodiazepine receptors among the fused 2-thiohydantoin derivatives, a series of 5-substituted imidazo[2,1-b]thiazepines was synthesized and investigated in radioligand binding studies at the benzodiazepine binding site of GABA(A) receptors in rat brain cortical membranes. Among ortho-substituted 5-arylidene-imidazo[2,1-b]thiazepines compounds could be identified which exhibit affinity for the benzodiazepine binding site at low micromolar concentrations. X-ray structure analyses for two compounds (6ae and 6ag) have been performed. In order to analyze the structure-activity relationships, 3D models of all compounds have been completed (using X-ray data). Physicochemical properties calculated (log P and log D) as well as experimental thin layer chromatography data were examined.

Pyrimidin-8-on[2,1-f]theophylline-9-alkylcarboxylic acids amides as A1 and A2A adenosine receptor ligands.

Starting from the appropriate esters (1-3), pyrimidin-8-on[2,1-f]theophylline-9-alkylcarboxylic acids amides (4-10) were synthesized and evaluated as hydrochlorides (4a-10a) for their affinity at brain A(1) and A(2A) adenosine receptor subtypes. Radioligand binding assay showed that morpholine-ethyl(-propyl) amide of pyrimidin-8-on[2,1-f]theophylline-9-acetic acid (4a, 5a) exhibited greater affinity and selectivity for A(1) and A(2A) receptors than parent compounds (theophylline and caffeine), with K(i) values: 12.2 and 3.1 microM for A(1) and 1.11 and 5.89 microM for A(2A), respectively. Morpholine-ethyl amide of pyrimidin-8-on[2,1-f]theophylline-9-propanoic acid (6a) and the dimethyl-amino analog (10a) exhibited much lower affinity for A(1) and A(2A) adenosine receptors, with K(i) values, respectively: 53.9 and 72.6 microM for A(1) and 120 and 115 microM for A(2A). Morpholine-propyl amide of pyrimidin-8-on[2,1-f]theophylline-9-propanoic acid (7a) exhibited relatively higher affinity for A(1) adenosine receptor with K(i) value 32.8 microM, comparable to caffeine, but it showed weaker affinity to A(2A) receptor. The variation of affinity at A(1) and A(2A) adenosine receptors depends on the structure of substituent in N9-position of fused tricyclic theophylline derivatives. The most interesting were morpholino-ethyl(-propyl) amides of pyrimidin-8-on[2,1-f]theophylline-9-acetic acid (4a, 5a). The longer alkylene chain (propylene) between amide nitrogen and the basic center (5a) resulted in higher A(1) but lower A(2A) receptor affinity.

Impact of the aryl substituent kind and distance from pyrimido[2,1-f]purindiones on the adenosine receptor selectivity and antagonistic properties.

Adenosine receptor (AR) antagonists belong to two major groups of compounds: xanthines and non-xanthines. Recently several annelated xanthine derivatives have been described as selective A(1), A(2A), A(2B) and A(3) ARs antagonists. Contrary to dipropyl derivatives, in the group of dimethyl (un)substituted arylalkyl pyrimido[2,1-f]purindiones selective mainly adenosine A(2A) receptor antagonists were identified. Their activity depended on aryl substitution and its distance from pyrimido[2,1-f]purindione.

2-Phenylimidazo[2,1-i]purin-5-ones: structure-activity relationships and characterization of potent and selective inverse agonists at Human A3 adenosine receptors.

Structure-activity relationships of 2-phenyl-imidazo[2,1-i]purin-5-ones as ligands for human A(3) adenosine receptors (ARs) were investigated. An ethyl group in the 8-position of the imidazoline ring of 4-methyl-2-phenyl-imidazopurinone leading to chiral compounds was found to increase affinity for human A(3) ARs by several thousand-fold. Propyl substitution instead of methyl at N4 decreased A(3) affinity but increased A(1) affinity leading to potent A(1)-selective AR antagonists. The most potent A(1) antagonist of the present series was (S)-8-ethyl-2-phenyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one (S-3) exhibiting a K(i) value of 7.4 nM at rat A(1) ARs and greater than 100-fold selectivity versus rat A(2A) and human A(3) ARs. At human A(1) ARs 2-phenylimidazo[2,1-i]purin-5-ones were generally less potent and therefore less A(1)-selective (S-3: K(i)=98 nM). 2-, 3-, or 4-Mono-chlorination of the 2-phenyl ring reduced A(3) affinity but led to an increase in affinity for A(1) ARs, whereas di- (3,4-dichloro) or polychlorination (2,3,5-trichloro) increased A(3) affinity. The most potent and selective A(3) antagonist of the present series was the trichlorophenyl derivative (R)-8-ethyl-4-methyl-2-(2,3,5-trichlorophenyl)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one (R-8) exhibiting a subnanomolar K(i) value at human A(3) ARs and greater than 800-fold selectivity versus the other AR subtypes. Methylation of 4-alkyl-2-phenyl-substituted imidazo[2,1-i]purin-5-ones led exclusively to the N9-methyl derivatives, which exhibited largely reduced AR affinities as compared to the unmethylated compounds. [35S]GTP gamma S binding studies of the most potent 2-phenyl-imidazo[2,1-i]purin-5-ones at membranes of Chinese hamster ovary cells expressing the human A(3) AR revealed that the compounds were inverse agonists at A(3) receptors under standard test conditions. Due to their high A(3) affinity, selectivity, and relatively high water-solubility, 2-phenyl-imidazo[2,1-i]purin-5-ones may become useful research tools.

Lignans isolated from valerian: identification and characterization of a new olivil derivative with partial agonistic activity at A(1) adenosine receptors.

A methanolic extract of the roots of Valeriana officinalis (valerian) was investigated for its lignan content. In addition to the lignans 8'-hydroxypinoresinol (1) and pinoresinol-4-O-beta-D-glucoside (2), which had already been isolated from valerian in an earlier study, the 7,9'-monoepoxylignans massoniresinol-4'-O-beta-D-glucoside (3), 4'-O-beta-D-glucosyl-9-O-(6' '-deoxysaccharosyl)olivil (4), and berchemol-4'-O-beta-D-glucoside (5) and the 7,9':7',9-diepoxylignans pinoresinol-4,4'-di-beta-O-D-glucoside (6), 8-hydroxypinoresinol-4'-O-beta-D-glucoside (7), and 8'-hydroxypinoresinol-4'-O-beta-D-glucoside (8) were identified. While lignans 3, 6, 7, and 8 had already been isolated from other plants, lignans 4 and 5 are new natural products. The lignans were investigated in radioligand binding assays at various receptors of the central nervous system, including GABA(A), benzodiazepine, 5-HT(1A), and adenosine A(1) and A(2A) receptors, to investigate their potential contribution to the pharmacological activity of valerian. The novel olivil derivative 4 proved to be a partial agonist at rat and human A(1) adenosine receptors exhibiting A(1) affinity and activity in low micromolar to submicromolar concentrations. Lignan 4 is the first nonnucleoside adenosine receptor agonist not structurally related to adenosine.

Interactions of valerian extracts and a fixed valerian-hop extract combination with adenosine receptors.

Phytopharmaceuticals and dietary supplements containing valerian are used as mild sleep-inducing agents. An in vitro radioligand binding assay at A(1) and A(2A) adenosine receptors (ARs) was conducted with a fixed extract combination of valerian and hop (Ze 91019) to investigate a possible mechanism for the pharmacological activity of the extract. Component extracts of valerian and hop were also individually investigated. The fixed combination Ze 91019 as well as the valerian extracts therein exhibited selective affinity to A(1)ARs (K(i) = 0.15-0.37 mg/mL vs [(3)H]CCPA). The same extracts exhibited partial agonist activity at the A(1) adenosine receptor as indicated by a lower degree of stimulation of [35S]GTP gamma S binding in membrane preparations of CHO-hA(1) cells as compared to the full A(1) AR agonist N(6)-cyclopentyladenosine (CPA). In addition valerian extract inhibited cAMP accumulation in CHO-hA(1) cell membranes. The partial agonistic activity at A(1)ARs may thus play a role in the sleep inducing effect of Ze 91019 and the valerian extract therein.

1,8-disubstituted xanthine derivatives: synthesis of potent A2B-selective adenosine receptor antagonists.

3-Unsubstituted xanthine derivatives bearing a cyclopentyl or a phenyl residue in the 8-position were synthesized and developed as A2B adenosine receptor antagonists. Compounds bearing polar substituents were prepared to obtain water-soluble derivatives. 1-Alkyl-8-phenylxanthine derivatives were found to exhibit high affinity for A2B adenosine receptors (ARs). 1,8-disubstituted xanthine derivatives were equipotent to or more potent than 1,3,8-trisubstituted xanthines at A2B ARs, but generally less potent at A1 and A2A, and much less potent at A3 ARs. Thus, the new compounds exhibited increased A2B selectivity versus all other AR subtypes. 9-Deazaxanthines (pyrrolo[2,3-d]pyrimidindiones) appeared to be less potent at A2B ARs than the corresponding xanthine derivatives. 1-Propyl-8-p-sulfophenylxanthine (17) was the most selective compound of the present series, exhibiting a K(i) value of 53 nM at human A2B ARs and showing greater than 180-fold selectivity versus human A1 ARs. Compound 17 was also highly selective versus rat A1 ARs (41-fold) and versus the other human AR subtypes (A2A > 400-fold and A3 > 180-fold). The compound is highly water-soluble due to its sulfonate function. 1-Butyl-8-p-carboxyphenylxanthine (10), another polar analogue bearing a carboxylate function, exhibited a K(i) value of 24 nM for A2B ARs, 49-fold selectivity versus human and 20-fold selectivity versus rat A1 ARs, and greater than 150-fold selectivity versus human A2A and A3 ARs. 8-[4-(2-Hydroxyethylamino)-2-oxoethoxy)phenyl]-1-propylxanthine (29) and 1-butyl-8-[4-(4-benzyl)piperazino-2-oxoethoxy)phenyl]xanthine (35) were among the most potent A2B antagonists showing K(i) values at A2B ARs of 1 nM, 57-fold (29) and 94-fold (35) selectivity versus human A1, ca. 30-fold selectivity versus rat A1, and greater than 400-fold selectivity versus human A2A and A3 ARs. The new potent, selective, water-soluble A2B antagonists may be useful research tools for investigating A2B receptor function.