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8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase.
Eur J Med Chem. 2011 Aug; 46(8):3474-85.EJ

Abstract

Recently it was reported that a series of 8-benzyloxycaffeine analogues are potent reversible inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to discover additional C8 oxy substituents of caffeine that lead to potent MAO inhibition, a series of related 8-aryl- and alkyloxycaffeine analogues were synthesized and their MAO-A and -B inhibition potencies were compared to those of the 8-benzyloxycaffeines. The results document that while the 8-substituted-oxycaffeine analogues inhibited both human MAO isoforms, they displayed a high degree of selectivity for MAO-B. 8-(3-Phenylpropoxy)caffeine, 8-(2-phenoxyethoxy)caffeine and 8-[(5-methylhexyl)oxy]caffeine were found to be the especially potent MAO-B inhibitors with IC(50) values ranging from 0.38 to 0.62 μM. These inhibitors are therefore 2.5-4.6 fold more potent MAO-B inhibitors than is 8-benzyloxycaffeine (IC(50) = 1.77 μM). It is also demonstrated that, analogous to 8-benzyloxycaffeine, halogen substitution on the phenyl ring of the C8 substituent significantly enhances MAO binding affinity. For example, the most potent MAO-B inhibitor of the present series is 8-[2-(4-bromophenoxy)ethoxy]caffeine with an IC(50) value of 0.166 μM. This study also reports possible binding orientations of selected oxy caffeines within the active site cavities of MAO-A and MAO-B.

Authors+Show Affiliations

Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21621312

Citation

Strydom, Belinda, et al. "8-Aryl- and Alkyloxycaffeine Analogues as Inhibitors of Monoamine Oxidase." European Journal of Medicinal Chemistry, vol. 46, no. 8, 2011, pp. 3474-85.
Strydom B, Bergh JJ, Petzer JP. 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase. Eur J Med Chem. 2011;46(8):3474-85.
Strydom, B., Bergh, J. J., & Petzer, J. P. (2011). 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase. European Journal of Medicinal Chemistry, 46(8), 3474-85. https://doi.org/10.1016/j.ejmech.2011.05.014
Strydom B, Bergh JJ, Petzer JP. 8-Aryl- and Alkyloxycaffeine Analogues as Inhibitors of Monoamine Oxidase. Eur J Med Chem. 2011;46(8):3474-85. PubMed PMID: 21621312.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase. AU - Strydom,Belinda, AU - Bergh,Jacobus J, AU - Petzer,Jacobus P, Y1 - 2011/05/12/ PY - 2011/04/21/received PY - 2011/05/05/revised PY - 2011/05/05/accepted PY - 2011/5/31/entrez PY - 2011/5/31/pubmed PY - 2011/10/1/medline SP - 3474 EP - 85 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 46 IS - 8 N2 - Recently it was reported that a series of 8-benzyloxycaffeine analogues are potent reversible inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to discover additional C8 oxy substituents of caffeine that lead to potent MAO inhibition, a series of related 8-aryl- and alkyloxycaffeine analogues were synthesized and their MAO-A and -B inhibition potencies were compared to those of the 8-benzyloxycaffeines. The results document that while the 8-substituted-oxycaffeine analogues inhibited both human MAO isoforms, they displayed a high degree of selectivity for MAO-B. 8-(3-Phenylpropoxy)caffeine, 8-(2-phenoxyethoxy)caffeine and 8-[(5-methylhexyl)oxy]caffeine were found to be the especially potent MAO-B inhibitors with IC(50) values ranging from 0.38 to 0.62 μM. These inhibitors are therefore 2.5-4.6 fold more potent MAO-B inhibitors than is 8-benzyloxycaffeine (IC(50) = 1.77 μM). It is also demonstrated that, analogous to 8-benzyloxycaffeine, halogen substitution on the phenyl ring of the C8 substituent significantly enhances MAO binding affinity. For example, the most potent MAO-B inhibitor of the present series is 8-[2-(4-bromophenoxy)ethoxy]caffeine with an IC(50) value of 0.166 μM. This study also reports possible binding orientations of selected oxy caffeines within the active site cavities of MAO-A and MAO-B. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/21621312/8_Aryl__and_alkyloxycaffeine_analogues_as_inhibitors_of_monoamine_oxidase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(11)00376-X DB - PRIME DP - Unbound Medicine ER -