Dual inhibition of monoamine oxidase B and antagonism of the adenosine A(2A) receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues

Bioorganic & Medicinal Chemistry
Judey PretoriusJacobus P Petzer

Abstract

The adenosine A(2A) receptor has emerged as an attractive target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonists of the A(2A) receptor (A(2A) antagonists) may be neuroprotective and may help to alleviate the symptoms of PD. We have reported recently that several members of the (E)-8-styrylcaffeine class of A(2A) antagonists also are potent inhibitors of monoamine oxidase B (MAO-B). Since MAO-B inhibitors are known to possess anti-parkinsonian properties, dual-target-directed drugs that block both MAO-B and A(2A) receptors may have enhanced value in the management of PD. In an attempt to explore this concept further we have prepared three additional classes of C-8 substituted caffeinyl analogues. The 8-phenyl- and 8-benzylcaffeinyl analogues exhibited relatively weak MAO-B inhibition potencies while selected (E,E)-8-(4-phenylbutadien-1-yl)caffeinyl analogues were found to be exceptionally potent reversible MAO-B inhibitors with enzyme-inhibitor dissociation constants (K(i) values) ranging from 17 to 149 nM. Furthermore, these (E,E)-8-(4-phenylbutadien-1-yl)caffeines acted as potent A(2A) antagonists with K(i) values ranging from 59 to 153 nM. We conclude that the (E,E)-8-(4-phenylbutadien-1-yl)c...Continue Reading

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Citations

Jan 25, 2012·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Vinogran NaidooBen A Bahr
Dec 27, 2008·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Jacobus P PetzerCornelis J Van der Schyf
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Jan 23, 2010·Bioorganic & Medicinal Chemistry·Belinda StrydomJacobus P Petzer
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Dec 10, 2013·The Journal of Pharmacy and Pharmacology·Anél PetzerJacobus P Petzer
Jan 3, 2020·Current Medicinal Chemistry·Ting YangHailin Cong
Apr 29, 2015·Journal of Medicinal Chemistry·Simone Carradori, Romano Silvestri
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Jul 23, 2011·Bioorganic & Medicinal Chemistry·Clarina I Manley-KingJacobus P Petzer
Apr 3, 2020·Combinatorial Chemistry & High Throughput Screening·Della G T Parambi

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