Dual inhibition of monoamine oxidase B and antagonism of the adenosine A(2A) receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues.
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)caffeines are a promising candidate class of dual-acting compounds.
Pretorius
Judey
J
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; D002070:Butadienes / Q000138:chemical synthesis / Q000494:pharmacology*; D002110:Caffeine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D058917:Adenosine A2 Receptor Antagonists; D002070:Butadienes; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D002110:Caffeine; D008995:Monoamine Oxidase