Inositol monophosphatase inhibitors--lithium mimetics?
Given the putative role of inositol monophosphatase (IMPase) as the molecular target for the therapeutic effects of lithium, inhibitors of this enzyme have been proposed to be lithium-mimetics. Although cation and natural product inhibitors of IMPase have been described, these have not proved suitable for cell culture studies due to a lack of specificity. On the other hand, substrate (inositol 1-phosphate)-based inhibitors have proved useful for showing that this class of compounds mimic lithium with respect to effects on the phosphatidylinositol (PI) cell-signaling pathway. However, since these compounds are highly charged, their polarity means they are not suitable for in vivo use. Finally, the recent elucidation of the structure and mechanism of IMPase may provide the opportunity to develop compounds which specifically interact with key structural and mechanistic features of the enzyme and would represent novel structure- or mechanism-based inhibitors.
Atack
J R
JR
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, England.
D004164:Diphosphonates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004164:Diphosphonates; D004791:Enzyme Inhibitors; C079103:L 690330; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase