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Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A1 and A2A receptor antagonists.
Bioorg Med Chem Lett. 2016 12 15; 26(24):5951-5955.BM

Abstract

Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A1 adenosine receptor antagonists, selected novel and known 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine and 1,3,7-trimethyl-8-(phenoxymethyl)-xanthine analogs were synthesized and evaluated for their A1 and A2A adenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A1 and A2A adenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A1 and A2A binding affinity. Overall it was found that para-substitution on the phenoxymethyl side-chain of the 1,3-diethyl-xanthines decreased A1 affinity except for the 4-Br analog (4f) exhibiting the best A1 affinity in the submicromolar range. On the other hand A2A affinity for the 1,3-diethyl-xanthines were increased with para-substitution and the 4-OCH3 (4b) analog showed the best A2A affinity with a Ki value of 237nM. The 1,3-diethyl-substituted analogs (4a, and 4f) behaved as A1 adenosine receptor antagonists in GTP shift assays performed with rat whole brain membranes expressing A1 adenosine receptors. This study concludes that para-substituted 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine analogs represent novel A1 and A2A adenosine receptor antagonists that are appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's and Alzheimer's disease.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Harmse R
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
van der Walt MM
Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Petzer JP
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Terre'Blanche G
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Electronic address: Gisella.Terreblanche@nwu.ac.za.

MeSH

Adenosine A1 Receptor AntagonistsAdenosine A2 Receptor AntagonistsAnimalsDose-Response Relationship, DrugDrug DiscoveryMolecular StructureRatsReceptor, Adenosine A1Receptor, Adenosine A2AStructure-Activity RelationshipXanthine

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27836398

Citation

Harmse, Rozanne, et al. "Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine Derivatives as Novel Adenosine A1 and A2A Receptor Antagonists." Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 24, 2016, pp. 5951-5955.
Harmse R, van der Walt MM, Petzer JP, et al. Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A1 and A2A receptor antagonists. Bioorg Med Chem Lett. 2016;26(24):5951-5955.
Harmse, R., van der Walt, M. M., Petzer, J. P., & Terre'Blanche, G. (2016). Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A1 and A2A receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 26(24), 5951-5955. https://doi.org/10.1016/j.bmcl.2016.10.086
Harmse R, et al. Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine Derivatives as Novel Adenosine A1 and A2A Receptor Antagonists. Bioorg Med Chem Lett. 2016 12 15;26(24):5951-5955. PubMed PMID: 27836398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A1 and A2A receptor antagonists. AU - Harmse,Rozanne, AU - van der Walt,Mietha M, AU - Petzer,Jacobus P, AU - Terre'Blanche,Gisella, Y1 - 2016/10/31/ PY - 2016/09/12/received PY - 2016/10/26/revised PY - 2016/10/28/accepted PY - 2016/11/12/pubmed PY - 2017/6/28/medline PY - 2016/11/13/entrez KW - 1,3,7-Trimethyl-8-(phenoxymethyl)-xanthines KW - 1,3-Diethyl-7-methyl-8-(phenoxymethyl)-xanthines KW - Adenosine A(1) and A(2A) receptor antagonists KW - Caffeine SP - 5951 EP - 5955 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 26 IS - 24 N2 - Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A1 adenosine receptor antagonists, selected novel and known 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine and 1,3,7-trimethyl-8-(phenoxymethyl)-xanthine analogs were synthesized and evaluated for their A1 and A2A adenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A1 and A2A adenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A1 and A2A binding affinity. Overall it was found that para-substitution on the phenoxymethyl side-chain of the 1,3-diethyl-xanthines decreased A1 affinity except for the 4-Br analog (4f) exhibiting the best A1 affinity in the submicromolar range. On the other hand A2A affinity for the 1,3-diethyl-xanthines were increased with para-substitution and the 4-OCH3 (4b) analog showed the best A2A affinity with a Ki value of 237nM. The 1,3-diethyl-substituted analogs (4a, and 4f) behaved as A1 adenosine receptor antagonists in GTP shift assays performed with rat whole brain membranes expressing A1 adenosine receptors. This study concludes that para-substituted 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine analogs represent novel A1 and A2A adenosine receptor antagonists that are appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's and Alzheimer's disease. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/27836398/Discovery_of_13_diethyl_7_methyl_8__phenoxymethyl__xanthine_derivatives_as_novel_adenosine_A1_and_A2A_receptor_antagonists_ DB - PRIME DP - Unbound Medicine ER -