Synthesis of (<i>E</i>)‑8-(3-Chlorostyryl)caffeine
Analogues Leading to 9‑Deazaxanthine Derivatives as Dual A<sub>2A</sub> Antagonists/MAO‑B Inhibitors
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Abstract
A systematic modification of the caffeinyl core and substituents
of the reference compound (<i>E</i>)-8-(3-chlorostyryl)caffeine
led to the 9-deazaxanthine derivative (<i>E</i>)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1<i>H</i>-pyrrolo[3,2-<i>d</i>]pyrimidine-2,4-(3<i>H</i>,5<i>H</i>)-dione (<b>17f</b>), which acts
as a dual human A<sub>2a</sub> antagonist/MAO-B inhibitor (<i>K</i><sub>i</sub>(A<sub>2A</sub>) = 260 nM; IC<sub>50</sub>(MAO-B)
= 200 nM; IC<sub>50</sub>(MAO-A) = 10 μM) and dose dependently
counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by
the oral route. The compound is the best balanced A<sub>2A</sub> antagonist/MAO-B
inhibitor reported to date, and it could be considered as a new lead
in the field of anti-Parkinson’s agents. A number of analogues
of <b>17f</b> were synthesized and qualitative SARs are discussed.
Two analogues of <b>17f</b>, namely <b>18b</b> and <b>19a</b>, inhibit MAO-B with IC<sub>50</sub> of 68 and 48 nM, respectively,
being 5–7-fold more potent than the prototypical MAO-B inhibitor
deprenyl (IC<sub>50</sub> = 334 nM)