- 1,3,7-Triethyl-substituted xanthines - Possess nanomolar affinity for the adenosine A1 receptor
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Adenosine A1 receptors are attracting great interest as drug targets for their role in cognitive deficits. Antagonism of the adenosine A1 receptor may offer therapeutic benefits in complex neurological diseases, such as Alzheimer's and Parkinson's disease. The aim of this study was to discover potential selective adenosine A1 receptor antagonists. Several analogs of 8-(3-phenylpropyl)xanthines (3), 8-(2-phenylethyl)xanthines (4) and 8-(phenoxymethyl)xanthines (5) were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that the 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d), among each series, displayed the highest affinity for the adenosine A1 receptor with Ki values in the nanomolar range. This ethyl-substitution pattern was previously unknown to enhance adenosine A1 receptor binding affinity. The 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d) behaved as adenosine A1 receptor antagonists in GTP shift assays performed with either rat cortical or whole brain membranes expressing adenosine A1 receptors. Further, in vivo evaluation of 3d showed reversal of adenosine A1 receptor agonist-induced hypolocomotion. In conclusion, the most potent evaluated compound, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (3d), showed both in vitro and in vivo activity, and therefore represent a novel adenosine A1 receptor antagonist that may have potential as a drug candidate for dementia disorders.
- Van Der Walt, Mietha M.,Terre'Blanche, Gisella
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p. 6641 - 6649
(2015/10/19)
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- SUBSTITUTED XANTHINES AND METHODS OF USE THEREOF
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Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.
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- Inhibition of monoamine oxidase by selected phenylalkylcaffeine analogues
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Objectives Caffeine represents a useful scaffold for the design of monoamine oxidase (MAO) type B inhibitors. Specifically, substitution on the C8 position yields structures which are high-potency MAO-B inhibitors. To explore the structure-activity relati
- Petzer, Anel,Grobler, Paul,Bergh, Jacobus J.,Petzer, Jacobus P.
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p. 677 - 687
(2014/05/06)
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- Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists
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Adenosine receptor antagonists that are selective for the A2A receptor subtype (A2A antagonists) are under investigation as possible therapeutic agents for the symptomatic treatment of the motor deficits associated with Parkinson's disease (PD). Results of recent studies in the MPTP mouse model of PD suggest that A2A antagonists may possess neuroprotective properties. Since monoamine oxidase B (MAO-B) inhibitors also enhance motor function and reduce MPTP neurotoxicity, we have examined the MAO-B inhibiting properties of several A2A antagonists and structurally related compounds in an effort to determine if inhibition of MAO-B may contribute to the observed neuroprotection. The results of these studies have established that all of the (E)-8-styrylxanthinyl derived A2A antagonists examined display significant MAO-B inhibitory properties in vitro with Ki values in the low μM to nM range. Included in this series is (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), a potent A2A antagonist and neuroprotective agent that is in clinical trials. The results of these studies suggest that MAO-B inhibition may contribute to the neuroprotective potential of A2A receptor antagonists such as KW-6002 and open the possibility of designing dual targeting drugs that may have enhanced therapeutic potential in the treatment of PD.
- Petzer, Jacobus P.,Steyn, Salome,Castagnoli, Kay P.,Chen, Jiang-Fan,Schwarzschild, Michael A.,Van Der Schyf, Cornelis J.,Castagnoli, Neal
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p. 1299 - 1310
(2007/10/03)
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