Removal of the phosphate group in mechanism-based inhibitors of inositol monophosphatase leads to unusual inhibitory activity.
Inositol monophosphatase is widely held to be the therapeutic target for inhibition by lithium ion in the treatment of bipolar disorder. In a continued effort to improve the bioavailability of alternative inhibitors, we have designed and tested two new series of compounds; phosphonates and product-like mimics. Phosphonate substrate mimics were competitive inhibitors of reduced potency as compared to phosphate based inhibitors. Product mimics however, showed various inhibitory modes of action. The 6-butylamino derivative 6p was an uncompetitive inhibitor when acting alone (K(i)= 0.3 mM) but displayed non-competitive inhibition in the presence of inorganic phosphate. This compound represents a new lead in the search for a viable replacement for lithium ion therapy.
Miller
David J
DJ
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, UK B15 2TT.
Bashir-Uddin Surfraz
M
M
Akhtar
Mahmoud
M
Gani
David
D
Allemann
Rudolf K
RK
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D018716:Molecular Mimicry / Q000502:physiology; D015394:Molecular Structure; D010710:Phosphates / Q000737:chemistry*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
D004791:Enzyme Inhibitors; D010710:Phosphates; D011994:Recombinant Proteins; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase