Search

Your search keyword '"Zoski K"' showing total 14 results
Start Over Author "Zoski K"
14 results on '"Zoski K"'

6. A Series of 6- and 7-Piperazinyl- and -Piperidinylmethylbenzoxazinones with Dopamine D4 Antagonist Activity:  Discovery of a Potential Atypical Antipsychotic Agent

Author

Belliotti, T. R., Wustrow, D. J., Brink, W. A., Zoski, K. T., Shih, Y.-H., Whetzel, S. Z., Georgic, L. M., Corbin, A. E., Akunne, H. C., Heffner, T. G., Pugsley, T. A., and Wise, L. D.

Abstract

As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure−activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.

Published
1999

9. Aminopyrimidines with High Affinity for Both Serotonin and Dopamine Receptors

Author

Wustrow, D., Belliotti, T., Glase, S., Kesten, S. R., Johnson, D., Colbry, N., Rubin, R., Blackburn, A., Akunne, H., Corbin, A., Davis, M. D., Georgic, L., Whetzel, S., Zoski, K., Heffner, T., Pugsley, T., and Wise, L.

Abstract

A series of {4-[2-(4-arylpiperazin-1-yl)alkyl]cyclohexyl}pyrimidin-2-ylamines was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.

Published
1998

12. Design, synthesis, and pharmacological evaluation of azetedine and pyrrolidine derivatives as dual norepinephrine reuptake inhibitors and 5-HT(1A) partial agonists.

Author

Pettersson M, Campbell BM, Dounay AB, Gray DL, Xie L, O'Donnell CJ, Stratman NC, Zoski K, Drummond E, Bora G, Probert A, and Whisman T

Subjects
Adrenergic Uptake Inhibitors pharmacokinetics, Animals, Anxiety drug therapy, Attention Deficit Disorder with Hyperactivity drug therapy, Azetidines chemistry, Azetidines pharmacokinetics, Azetidines pharmacology, Brain metabolism, Depressive Disorder drug therapy, Dogs, Humans, Pyrrolidines chemistry, Pyrrolidines pharmacokinetics, Pyrrolidines pharmacology, Serotonin 5-HT1 Receptor Agonists pharmacokinetics, Adrenergic Uptake Inhibitors chemistry, Adrenergic Uptake Inhibitors pharmacology, Norepinephrine metabolism, Receptor, Serotonin, 5-HT1A metabolism, Serotonin 5-HT1 Receptor Agonists chemistry, Serotonin 5-HT1 Receptor Agonists pharmacology
Abstract

Compounds with combined norepinephrine reuptake inhibitor (NRI) and serotonin 1A (5-HT(1A)) partial agonist pharmacology may offer a new therapeutic approach for treating symptoms of neuropsychiatric disorders including ADHD, depression, and anxiety. Herein we describe the design and optimization of novel chemical matter that exhibits favorable dual NRI and 5-HT(1A) partial agonist activity. Lead compounds in this series were found to be devoid of activity at the dopamine transporter and were shown to be brain penetrant with high receptor occupancy., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Published
2011
Full Text
View/download PDF

13. Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists.

Author

Dounay AB, Barta NS, Campbell BM, Coleman C, Collantes EM, Denny L, Dutta S, Gray DL, Hou D, Iyer R, Maiti SN, Ortwine DF, Probert A, Stratman NC, Subedi R, Whisman T, Xu W, and Zoski K

Subjects
Adrenergic Uptake Inhibitors metabolism, Adrenergic Uptake Inhibitors pharmacology, Cell Line, Crystallography, X-Ray, Drug Evaluation, Preclinical methods, Humans, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Norepinephrine Plasma Membrane Transport Proteins metabolism, Phenols chemical synthesis, Phenols metabolism, Phenols pharmacology, Pyridines metabolism, Pyridines pharmacology, Receptor, Serotonin, 5-HT1A metabolism, Serotonin Receptor Agonists metabolism, Serotonin Receptor Agonists pharmacology, Adrenergic Uptake Inhibitors chemical synthesis, Drug Design, Norepinephrine Plasma Membrane Transport Proteins antagonists & inhibitors, Pyridines chemical synthesis, Serotonin 5-HT1 Receptor Agonists, Serotonin Receptor Agonists chemical synthesis
Abstract

Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Published
2010
Full Text
View/download PDF

14. 3-arylimino-2-indolones are potent and selective galanin GAL3 receptor antagonists.

Author

Konkel MJ, Lagu B, Boteju LW, Jimenez H, Noble S, Walker MW, Chandrasena G, Blackburn TP, Nikam SS, Wright JL, Kornberg BE, Gregory T, Pugsley TA, Akunne H, Zoski K, and Wise LD

Subjects
Animals, Binding, Competitive, Brain metabolism, COS Cells, Chlorocebus aethiops, Cyclic AMP biosynthesis, Humans, Imines pharmacokinetics, Imines pharmacology, Indoles pharmacokinetics, Indoles pharmacology, Ligands, Radioligand Assay, Rats, Receptor, Galanin, Type 1 drug effects, Receptor, Galanin, Type 2 drug effects, Stereoisomerism, Structure-Activity Relationship, Imines chemical synthesis, Indoles chemical synthesis, Receptor, Galanin, Type 3 antagonists & inhibitors
Abstract

A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a broad panel of targets, including GAL1 and GAL2. Compound 9 was also shown to be an antagonist in a human GAL3 receptor functional assay (Kb=29 nM).

Published
2006
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results