Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC).
The adenosine A2A receptor has emerged as a possible target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonism of the A2A 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 A2A receptor antagonists (A2A 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 A2A antagonists. Since MAO-B inhibitors are also thought to possess antiparkinsonian properties, dual targeting drugs that block both MAO-B and A2A 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 (pi), and the Hammett constant (sigma(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 (pi) being the principal substituent descriptors.
Vlok
Nevil
N
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Malan
Sarel F
SF
Castagnoli
Neal
N
Bergh
Jacobus J
JJ
Petzer
Jacobus P
JP
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002110:Caffeine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000187:drug effects* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
D058917:Adenosine A2 Receptor Antagonists; D008996:Monoamine Oxidase Inhibitors; C081320:8-(3-chlorostyryl)caffeine; D002110:Caffeine; D008995:Monoamine Oxidase