Inhibition of monoamine oxidase B by analogues of the adenosine A_(2A) receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC)

摘要

The adenosine A_(2A) receptor has emerged as a possible target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonism of the A_(2A) receptor not only improves the symptoms of the disease but may also protect against the underlying degenerative processes. We have recently reported that several known adenosine A_(2A) receptor antagonists (A_(2A) antagonists) also are moderate to very potent inhibitors of monoamine oxidase B (MAO-B). The most potent among these was (E)-8-(3-chlorostyryl)caffeine (CSC), a compound frequently used when examining the in vivo pharmacological effects of A_(2A) antagonists. Since MAO-B inhibitors are also thought to possess antiparkinsonian properties, dual targeting drugs that block both MAO-B and A_(2A) receptors may have enhanced therapeutic potential in the treatment of PD. In this study, we prepared selected analogues of CSC in an attempt to examine specific structural features that may be important for potent MAO-B inhibition. The results of a SAR study established that the potency of MAO-B inhibition by (E)-8-styrylcaffeinyl analogues depends upon the van der Waals volume (V_w), lipophilicity (π), and the Hammett constant (σ_m) of the substituents attached to C-3 of the phenyl ring of the styryl moiety. Potency also varies with substituents attached to C-4 with bulkiness (V_w) and lipophilicity (π) being the principal substituent descriptors.