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4. Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells

Author

Coldwell, M C, Boyfield, I, Brown, A M, Stemp, G, and Middlemiss, D N

Subjects
Amiloride, Receptors, Dopamine D2, Cricetinae, Papers, Dopamine Agonists, Receptors, Dopamine D4, Receptors, Dopamine D3, Animals, Dopamine Antagonists, Humans, CHO Cells, Binding, Competitive
Abstract

This study characterized pharmacologically the functional responses to agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in cloned cells using the cytosensor microphysiometer. Dopaminergic receptor agonists caused increases in extracellular acidification rate in adherent Chinese hamster ovary (CHO) clones expressing hD2, hD3 or hD4 receptors. Acidification rate responses to agonists in other cell lines expressing these receptors were smaller than those in adherent CHO cells. The time courses and maximum increases in acidification rate of the agonist responses in adherent CHO cells were different between the three dopamine receptor clones. Responses were blocked by pretreatment of cells with pertussis toxin or amiloride analogues. Most agonists had full intrinsic activity at each of the dopamine receptor subtypes, as compared to quinpirole, however both enantiomers of UH-232 and (-)3-PPP were partial agonists in this assay system. The functional potency of full agonists at each of the three receptors expressed in CHO cells was either higher than, or similar to, the apparent inhibition constants (Ki) determined in [125I]-iodosulpride competition binding studies. Functional selectivities of the agonists were less than radioligand binding selectivities. The rank orders of agonist potencies and selectivities were similar, but not identical, to the rank orders of radioligand binding affinities and selectivities. The dopamine receptor antagonists, iodosulpride and clozapine, had no effect on basal acidification rates but inhibited acidification responses in CHO cells to quinpirole in an apparently competitive manner. Antagonist potencies closely matched their radioligand binding affinities in these cells.

Published
1999

5. Modern Medicinal Chemistry

Author

Stemp, G.

Subjects
Modern Medicinal Chemistry (Book) -- Book reviews, Books -- Book reviews, Biological sciences, Chemistry, Pharmaceuticals and cosmetics industries
Published
1994

15. Human BACE-1 in complex with N-((1S,2R)-3-(cyclohexylamino)-2-hydroxy- 1-(phenylmethyl)propyl)-3-(ethylamino)-5-(2-oxo-1-pyrrolidinyl) benzamide

Author

Clarke, B., primary, Demont, E., additional, Dingwall, C., additional, Dunsdon, R., additional, Faller, A., additional, Hawkins, J., additional, Hussain, I., additional, MacPherson, D., additional, Maile, G., additional, Matico, R., additional, Milner, P., additional, Mosley, J., additional, Naylor, A., additional, O'Brien, A., additional, Redshaw, S., additional, Riddell, D., additional, Rowland, P., additional, Soleil, V., additional, Smith, K., additional, Stanway, S., additional, Stemp, G., additional, Sweitzer, S., additional, Theobald, P., additional, Vesey, D., additional, Walter, D.S., additional, Ward, J., additional, and Wayne, G., additional

Published
2008
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16. Human BACE-1 in complex with N-((1S,2R)-3-(((1S)-2-(cyclohexylamino)- 1-methyl-2-oxoethyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-3-(pentylsulfonyl)benzamide

Author

Clarke, B., primary, Demont, E., additional, Dingwall, C., additional, Dunsdon, R., additional, Faller, A., additional, Hawkins, J., additional, Hussain, I., additional, MacPherson, D., additional, Maile, G., additional, Matico, R., additional, Milner, P., additional, Mosley, J., additional, Naylor, A., additional, O'Brien, A., additional, Redshaw, S., additional, Riddell, D., additional, Rowland, P., additional, Soleil, V., additional, Smith, K., additional, Stanway, S., additional, Stemp, G., additional, Sweitzer, S., additional, Theobald, P., additional, Vesey, D., additional, Walter, D.S., additional, Ward, J., additional, and Wayne, G., additional

Published
2008
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17. Human BACE-1 in complex with N-((1S,2R)-1-benzyl-2-hydroxy-3-((1,1,5- trimethylhexyl)amino)propyl)-3-(ethylamino)-5-(2-oxopyrrolidin-1-yl) benzamide

Author

Clarke, B., primary, Demont, E., additional, Dingwall, C., additional, Dunsdon, R., additional, Faller, A., additional, Hawkins, J., additional, Hussain, I., additional, MacPherson, D., additional, Maile, G., additional, Matico, R., additional, Milner, P., additional, Mosley, J., additional, Naylor, A., additional, O'Brien, A., additional, Redshaw, S., additional, Riddell, D., additional, Rowland, P., additional, Soleil, V., additional, Smith, K., additional, Stanway, S., additional, Stemp, G., additional, Sweitzer, S., additional, Theobald, P., additional, Vesey, D., additional, Walter, D.S., additional, Ward, J., additional, and Wayne, G., additional

Published
2008
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18. Human BACE-1 in complex with N-((1S,2R)-3-(((1S)-2-(cyclohexylamino)- 1-methyl-2-oxoethyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-3-(2-oxo- 1-pyrrolidinyl)-5-(propyloxy)benzamide

Author

Clarke, B., primary, Demont, E., additional, Dingwall, C., additional, Dunsdon, R., additional, Faller, A., additional, Hawkins, J., additional, Hussain, I., additional, MacPherson, D., additional, Maile, G., additional, Matico, R., additional, Milner, P., additional, Mosley, J., additional, Naylor, A., additional, O'Brien, A., additional, Redshaw, S., additional, Riddell, D., additional, Rowland, P., additional, Soleil, V., additional, Smith, K., additional, Stanway, S., additional, Stemp, G., additional, Sweitzer, S., additional, Theobald, P., additional, Vesey, D., additional, Walter, D.S., additional, Ward, J., additional, and Wayne, G., additional

Published
2008
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19. Human BACE-1 in complex with 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin- 2-yl)-5-(ethylamino)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(1,2,3,4- tetrahydro-1-naphthalenylamino)propyl)benzamide

Author

Beswick, P., primary, Charrier, N., additional, Clarke, B., additional, Demont, E., additional, Dingwall, C., additional, Dunsdon, R., additional, Faller, A., additional, Gleave, R., additional, Hawkins, J., additional, Hussain, I., additional, Johnson, C.N., additional, Macpherson, D., additional, Maile, G., additional, Matico, R., additional, Milner, P., additional, Mosley, J., additional, Naylor, A., additional, O'Brien, A., additional, Redshaw, S., additional, Riddell, D., additional, Rowland, P., additional, Skidmore, J., additional, Soleil, V., additional, Smith, K.J., additional, Stanway, S., additional, Stemp, G., additional, Stuart, A., additional, Sweitzer, S., additional, Theobald, P., additional, Vesey, D., additional, Walter, D.S., additional, Ward, J., additional, and Wayne, G., additional

Published
2008
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20. Human BACE-1 in complex with N-((1S,2R)-3-(((1S)-2-(cyclohexylamino)- 1-methyl-2-oxoethyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-3-(ethylamino)-5-(2-oxo-1-pyrrolidinyl)benzamide

Author

Clarke, B., primary, Demont, E., additional, Dingwall, C., additional, Dunsdon, R., additional, Faller, A., additional, Hawkins, J., additional, Hussain, I., additional, MacPherson, D., additional, Maile, G., additional, Matico, R., additional, Milner, P., additional, Mosley, J., additional, Naylor, A., additional, O'Brien, A., additional, Redshaw, S., additional, Riddell, D., additional, Rowland, P., additional, Soleil, V., additional, Smith, K., additional, Stanway, S., additional, Stemp, G., additional, Sweitzer, S., additional, Theobald, P., additional, Vesey, D., additional, Walter, D.S., additional, Ward, J., additional, and Wayne, G., additional

Published
2008
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21. Human BACE-1 in complex with 3-(ethylamino)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((3-(trifluoromethyl)phenyl)methyl)amino)propyl)-5-(2-oxo-1-pyrrolidinyl)benzamide

Author

Clarke, B., primary, Demont, E., additional, Dingwall, C., additional, Dunsdon, R., additional, Faller, A., additional, Hawkins, J., additional, Hussain, I., additional, MacPherson, D., additional, Maile, G., additional, Matico, R., additional, Milner, P., additional, Mosley, J., additional, Naylor, A., additional, O'Brien, A., additional, Redshaw, S., additional, Riddell, D., additional, Rowland, P., additional, Soleil, V., additional, Smith, K., additional, Stanway, S., additional, Stemp, G., additional, Sweitzer, S., additional, Theobald, P., additional, Vesey, D., additional, Walter, D.S., additional, Ward, J., additional, and Wayne, G., additional

Published
2008
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22. Pharmacokinetics of the novel, high-affinity and selective dopamine D3 receptor antagonist SB-277011 in rat, dog and monkey:in vitro/in vivocorrelation and the role of aldehyde oxidase

Author

Austin, N. E., primary, Baldwin, S. J., additional, Cutler, L., additional, Deeks, N., additional, Kelly, P. J., additional, Nash, M., additional, Shardlow, C. E., additional, Stemp, G., additional, Thewlis, K., additional, Ayrton, A., additional, and Jeffrey, P., additional

Published
2001
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31. Pharmacokinetics of the novel, high-affinity and selective dopamine D3 receptor antagonist SB-277011 in rat, dog and monkey: in vitro/in vivo correlation and the role of aldehyde oxidase.

Author

Austin, N. E., Baldwin, S. J., Cutler, L., Deeks, N., Kelly, P. J., Nash, M., Shardlow, C. E., Stemp, G., Thewlis, K., Ayrton, A., and Jeffrey, P.

Subjects
DOPAMINE antagonists, LIVER cells, PHYSIOLOGY, CHEMICALS
Abstract

1. In vitro studies with the selective dopamine D3 receptor antagonist SB-277011 were conducted in liver microsomes and homogenates from rat, dog, cynomolgus monkey and human to correlate the rate of metabolism with the in vivo pharmacokinetics of the compound in rat, dog and cynomolgus monkey. 2. In the presence of NADPH, SB-277011 was relatively stable in the presence of liver microsomes from rat, dog, cynomolgus monkey and human with an intrinsic clearance (CL[sub i]) of <2ml min[sup -1] g[sup -1] liver for all species. In total liver homogenates, SB-277011 was metabolized at a similar rate in rat and dog (CL[sub i] <2mlmin[sup -1] g[sup -1] liver) to that in liver microsomes but in cynomolgus monkey and human (CL[sub i] = 9.9 and 45 mlmin [sup -1] g-[sup -1] liver, respectively) the intrinsic clearance was ~6- and 35-fold higher, respectively, than that in liver microsomes. 3. In the absence of NADPH, SB-277011 was rapidly cleared in liver homogenates from cynomolgus monkey and human (CL[sub i] = 7.4 and 27ml min[sup -1] g[sup -1] liver, respectively) demonstrating that a significant pathway of metabolism of this compound was via an NADPH-independent non-microsomal oxidative route. This pathway was sensitive to inhibition with isovanillin suggesting that the enzyme responsible was aldehyde oxidase. 4. The in vivo pharmacokinetics showed that the plasma clearance of SB-277011 was low in rat (20 mlmin[sup -1] kg[sup -1]), moderate in dog (14 mlmin[sup -1] kg[sup -1]) and high in cynomolgus monkey (58 mlmin[sup -1] kg[sup -1]), which is consistent with the in vitro findings and demonstrated a greater capacity for the monkey to metabolize this compound. The oral bioavailability of SB-277011 in rat, dog and cynomolgus monkey was 35, 43 and 2%, respectively. Given the high clearance of this compound in cynomolgus monkey, the low oral bioavailability is probably as a result of high first-pass elimination, specifically by aldehyde oxidase, rather than poor absorption. 5. The high in vitro clearance of SB-277011 in human liver homogenates and the involvement of aldehyde oxidase in the metabolism of SB-277011 indicates that the bioavailability of the compound is likely to be low in human. [ABSTRACT FROM AUTHOR]

Published
2001
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35. Design and Synthesis of trans-3-(2-(4-((3-(3-(5-Methyl-1,2,4-oxadiazolyl))- phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro- 1H-3-benzazepine (SB-414796):  A Potent and Selective Dopamine D<INF>3</INF> Receptor Antagonist

Author

Macdonald, G. J., Branch, C. L., Hadley, M. S., Johnson, C. N., Nash, D. J., Smith, A. B., Stemp, G., Thewlis, K. M., Vong, A. K. K., Austin, N. E., Jeffrey, P., Winborn, K. Y., Boyfield, I., Hagan, J. J., Middlemiss, D. N., Reavill, C., Riley, G. J., Watson, J. M., Wood, M., Parker, S. G., and Ashby, C. R., Jr.

Abstract

At their clinical doses, current antipsychotic agents share the property of both dopamine D2 and D3 receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D2 receptor antagonism. Consequently, a selective dopamine D3 receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D3 receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D3 affinity and selectivity vs D2 with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D3 receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.

Published
2003

36. Design and Synthesis of trans-N-[4-[2-(6-Cyano-1,2,3,4-tetrahydroisoquinolin-2- yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011):  A Potent and Selective Dopamine D<INF>3</INF> Receptor Antagonist with High Oral Bioavailability and CNS Penetration in the Rat

Author

Stemp, G., Ashmeade, T., Branch, C. L., Hadley, M. S., Hunter, A. J., Johnson, C. N., Nash, D. J., Thewlis, K. M., Vong, A. K. K., Austin, N. E., Jeffrey, P., Avenell, K. Y., Boyfield, I., Hagan, J. J., Middlemiss, D. N., Reavill, C., Riley, G. J., Routledge, C., and Wood, M.

Abstract

A selective dopamine D3 receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3,4-tetrahydroisoquinolines, exemplified by 13, was identified with high D3 affinity and selectivity against the D2 receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (24, SB-277011). This compound is a potent and selective dopamine D3 receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D3 receptor in the CNS.

Published
2000

40. The separation of the enantiomers of some potassium channel activators on α1-acid glycoprotein: the effect of solute conformationglycoprotein: the effect of solute conformation

Author

Smith, R., Smith, D., Evans, J., and Stemp, G.

Abstract

The amide conformers of two compounds and their enantiomers have been separated by liquid chromatography on an α1-acid glycoprotein column. The effects of organic modifier and pH on the separations obtained were investigated. The conformers of one of the compounds were separated micro-preparatively at low temperature on the same column using a D2O-based eluent; D2O had no deleterious effects on the chromatography obtained. Some preliminary competition experiments on one of the amides and a close analogue are presented.

Published
1993
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