Planta Med 2012; 78 - P_104
DOI: 10.1055/s-0032-1307612

Mechanism and Kinetics of Inhibition of Human MAO A and B by Aplysinopsin Analogs

ND Chaurasiya 1, K Lewellyn 3, D Bialonska 4, J Zjawiony 3, BL Tekwani 1, 2
  • 1National Center for Natural Products Research
  • 2Department of Pharmacology
  • 3Department of Phamacognosy, School of Pharmacy, University of Mississippi, University MS 38677
  • 4Institute of Environmental Sciences, Jagiellonian University, 30–387, Krakow, Poland

Aplysinopsins are tryptophan-derived marine natural products isolated from numerous genera of sponges and scleractinian corals. Natural analogs differ in the bromination pattern of the indole ring as well as in the number and position of N-methylations of the imidazolidinone ring. Aplysinopsins have received considerable attention as promising neuromodulators with significant affinity to serotonin receptors and the potential to inhibit MAO activity. Recent SAR investigations through synthesis and evaluation of a series of aplysinopsins analogs identified three analogs with highly potent inhibition of human rMAO A and B. The lead analogs (1–3), were further evaluated for kinetic characteristics and mechanism of inhibition of human MAO A and B. In general the aplysinopsin analogs were more potent inhibitors of MAO A than B. The analog 1 was identified as the most potent inhibitor of MAO A with IC50 value of 5.6 nM. Analog 1 was 80 fold more selective for inhibition for MAO A than B.

Analog 1 inhibited MAO A through a reversible competitive mechanism with Ki value in the range of 13.5 to 18. 9 nM, while the analog 2 inhibited MAO A through a reversible mixed-type inhibition mechanism with Ki value in the range of 20.7 to 26.2 nM. The analog 2 and 3 showed only 4.5 and 11.0 fold selectivity for inhibition of MAO A than for MAO B. The analogs 1–3 inhibited MAO B through a reversible uncompetitive mechanism with Ki values in the range of 0.185 to 1.648µM. These results warrant further evaluation of lead aplysinopsins analogs as potential neuromodulators and their application in the treatment of neurological disorders.