The synthesis and evaluation of caffeine analogues as inhibitors of monoamine oxidase B and antagonists of the adenosine A₂A receptor

Abstract

The adenosine A2A receptor has emerged as an attractive target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonists of the A2A receptor (A2A antagonists) partially alleviate the symptoms of PD, prevent the development of motor complications and may also slow the underlying neurodegenerative process. It was recently reported that several members of the (E)-8-styrylcaffeine class of A2A antagonists also are potent inhibitors of monoamine oxidase B (MAO-B). Since MAO-B inhibitors have also been employed as anti-parkinsonian agents, dual-targetdirected drugs that block both MAO-B and A2A receptors may have enhanced value in the management of PD. In an attempt to identify additional dual-acting compounds, we have, in the present study, synthesised 3 additional classes of C-8 substituted caffeine analogues. While 8-phenyl- and 8-benzylcaffeines exhibited relatively weak MAO-B inhibition potencies, selected (£,£)-8-(4-phenylbutadien-1 -yl)caffeine analogues and the expansion of the series with ethyl substitution at positions 1,3 and 7 of the caffeine ring were found to be exceptionally potent reversible inhibitors with enzyme-inhibitor dissociation constants (K\ values) ranging from 17-149 nM. Furthermore, these (£,£)-8-(4-phenylbutadien-l-yl)caifeines also acted as potent A2A antagonists with K, values ranging from 59-153 nM. We conclude that (E,E)-$-(4-phenylbutadien-l-yl)caffeines are a promising candidate class of dual-acting compounds. In this study we also compared experimentally obtained K\ values for reversible interaction with MAO-B with experimentally obtained IC50 values (concentration of inhibitor producing 50% inhibition) and test the validity of the Cheng-Prusoff equation which relates these two parameters. The results of this study showed that the Cheng-Prusoff equation may be used to interconvert IC50 and K\values. In conclusion, this study has identified (£,is)-8-(4-phenylbutadien-l-yl)caffeines as a new class of adenosine A2A antagonists. These compounds have potencies similar to that of (E)-8-(3-chlorostyryl)caffeine (CSC), an A2A antagonist used as reference in pharmacological studies. The most potent A2A antagonist of the series, (£,£)-1,3- diethyl-8-(4-phenylbutadien-l-yl)-7-methylxanthine, antagonized A2A receptors with a potency similar to that of (£)-l,2-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), an A2A antagonist that is currently clinically evaluated asantiparkinsonian agent. Among the (£,£)-8-(4-pheny Ibutadien-1 -yl)caffeines analogues, we have also identified congeners with potent MAO-B inhibition properties. These compounds were exceptionally potent reversible MAO-B inhibitors with K\ values in the low nanomolar range. We therefore conclude that (E,E)-8-(4-phenylbutadien-l-yl)caffeines are potent A2A antagonists and MAO-B inhibitors. Since both these activities are relevant to PD, the compounds identified here may act as useful antiparkinsonian agents.