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H Wynn

Publications and source records attributed to H Wynn.

9 recordsLinked to original sources
PubMed2003

Data assimilation in the decision support system rodos.

Model predictions for a rapid assessment and prognosis of possible radiological consequences after an accidental release of radionuclides play an important role in nuclear emergency management. Radiological observations, e.g. dose rate measurements, can be used to improve such model predictions. The process of combining model predictions and observations, usually referred to as data assimilation, is described in this article within the framework of the real time on-line decision support system (RODOS) for off-site nuclear emergency management in Europe. Data assimilation capabilities, based on Kalman filters, are under development for several modules of the RODOS system, including the atmospheric dispersion, deposition, food chain and hydrological models. The use of such a generic data assimilation methodology enables the propagation of uncertainties throughout the various modules of the system. This would in turn provide decision makers with uncertainty estimates taking into account both model and observation errors. This paper describes the methodology employed as well as results of some preliminary studies based on simulated data.

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PubMed1988

Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety.

Calcium channel antagonist activities of the 1,2-dihydropyridines (9) were determined using the muscarinic-receptor mediated Ca2+ dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative potency order for 4-substituted analogs 9 was phenyl greater than 3-trifluoromethyl(nitro)phenyl greater than 4- and 2-trifluoromethyl(nitro)phenyl. Increasing the size of the alkyl ester substituents (9h) enhanced activity. The test results indicate that the 1,2-dihydropyridyl ring system (9) is partially bioisosteric with the 1,4-dihydropyridyl ring system (10). Competitive [3H]-nitrendipine binding studies indicated that the affinities of the 1,2-dihydropyridine analogues were much lower than expected from their ID50 activities, suggesting that these analogues inhibit calcium channels by a different receptor mechanism. In the synthetic work, Hantzsch condensation of aldehydes (3) with alkyl acetoacetates (4) afforded 3,5-dialkyl 2,6-dimethyl-4-(substituted-phenyl)-1,4-dihydropyridine-3,5-dicarboxylat es (5). Oxidation of 5 gave the aromatic pyridines (6) which were elaborated to the l-methylpyridinium methyl sulphates (7) and then to the perchlorates (8). Sodium borohydride reduction of 8 in aqueous ethanol gave 3,5-dialkyl 1,2,6-trimethyl-4-(substituted-phenyl)-1,2-dihydropyridine-3, 5-dicarboxylates (9).

Animals↗
PubMed1988

Synthesis and calcium channel antagonist activity of 1,2-dihydropyridyl analogues of nifedipine.

Calcium channel antagonist activities of 1,2-dihydropyridines (10), including that (10d) isomeric with nifedipine, were determined using the muscarinic-receptor mediated Ca2+ dependent contraction of guinea pig ileal longitudinal smooth muscle. The effect of the 4-substituent (R) on potency was cyclohexyl and phenyl greater than 2-,3- or 4-trifluoromethyl(nitro)phenyl, although the differences in activity were small. The nature of the 4-substituent (alkyl, cycloalkyl, aryl), and the position (ortho, meta, para) of further substituents (CF3 or NO2) in the case of 4-phenyl substitution, were not major determinants of activity. The weaker calcium channel antagonist activity of these compounds, relative to nifedipine, is attributed to differences in conformation between the 1,2- and 1,4-dihydropyridine ring systems and the orientation of the 4-aryl substituent. In the synthetic work, the required 1,2-dihydropyridines (10), were synthesized by a route involving regiospecific ortho-directed reduction of the 1-oxide analogues (9) using borane. NMR spectrometric studies indicated that the 4-(2-trifluoromethyl) analogue (10a) exists as a single rotamer (10a'), whereas the 4-(2-nitrophenyl) analogue (10d) exists as a 10:3 mixture of rotamers (10d') and (10d") at 25 degrees C in CDCl3 solution.

Animals↗
PubMed1987

Synthesis and calcium channel antagonist activity of dialkyl 4- (dihydropyridinyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylates.

The sodium borohydride reduction of 3,5-disubstituted 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)pyridines 2 and 5 in the presence of methyl, phenyl, or tert-butyl chloroformate afforded the respective 4-(dihydropyridinyl)-1,4-dihydropyridines 4 and 6 in good yield. Products 4 comprised a mixture of the 1,2- and 1,6-dihydropyridinyl regioisomers 4a and 4b where 4a was always the predominant regioisomer. Compounds possessing a 4-[dihydro-1-(phenoxycarbonyl)-3-pyridinyl] substituent, such as 26, were also a mixture of two regioisomers 26a and 26b, and each regioisomer existed as a mixture of two rotamers in Me2SO-d6 at 25 degrees C (26a', 26a'', and 26b', 26b'') due to restricted rotation about the nitrogen-to-carbonyl carbamate bond. The calcium antagonist activities for 4 and 6 were determined by using the muscarinic receptor-mediated Ca2+-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative order of activities for the 4-(dihydropyridinyl) analogues was 4-(dihydro-3-pyridinyl) greater than 4-(dihydro-4-pyridinyl). Increasing the size of the C-3(5) alkyl ester substituents increased activity. Compounds having nonidentical ester substituents were more active than those having identical ester substituents. Replacement of the C-3 and/or C-5 ester substituents by a cyano substituent(s) decreased activity significantly. An approximate 1:1 correlation between the IC50 value for inhibition of [3H]nitrendipine binding and inhibition of the tonic component of the muscarinic-induced contractile response was observed. The test results suggest that a 4-(dihydropyridinyl) substituent is bioisosteric with a 4-(nitrophenyl) substituent on a 1,4-dihydropyridine ring where m- and p-nitrophenyl are bioisosteric with the 4-[1,2(1,6)-dihydro-3-pyridinyl] 4 and 4-(1,2-dihydro-4-pyridinyl) 6 isomers, respectively.

Animals↗
PubMed1986

Synthesis and calcium channel antagonist activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-3,5-pyridinedicarboxylates.

The Hantzsch condensation of alkyl acetoacetates 3 with methyl 3-aminocrotonate (4) and pyridinecarboxaldehydes 5 afforded the unsymmetrical alkyl methyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-3,5-pyridinedicarboxylates 6, whereas condensation of 3 with 5 and ammonium hydroxide gave the symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-3,5-pyridinedicarboxylates 7. The calcium channel antagonist activities of disubstituted 1,4-dihydro-3,5-pyridinedicarboxylates 6,7, and 9 were determined with use of the muscarinic-receptor-mediated Ca2+-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative potency order for isomeric pyridinyl analogues 6 and 7 was 2-pyridinyl greater than 3-pyridinyl greater than 4-pyridinyl. Increasing the size of the alkyl ester substituents enhanced activity. Compounds having nonidentical ester substituents were more potent than those having identical ester substituents. Replacement of the C-3 and/or C-5 ester substituent(s) by a cyano substituent(s) decreased activity significantly. An approximate 1:1 correlation between the IC50 value for inhibition of [3H]nitrendipine binding and inhibition of the tonic component of the muscarinic-induced contractile response was observed. The test results suggest that a 4-(pyridinyl) substituent is bioisosteric with a 4-(nitrophenyl) substituent on a 1,4-dihydropyridine ring system where o-, m-, and p-nitrophenyl are bioisosteric with 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, respectively.

Animals↗