title: Probicyclophosphates: monocyclophosphates as potential prodrugs for bicyclophosphate GABA antagonists.
abstract: 4-Alkylbicyclophosphates, R1C(CH2O)3P(O), with suitable R1 substituents (e.g., t-butyl, isopropyl, or cyclohexyl) are highly toxic compounds [mouse intraperitoneal (ip) LD50 values 0.036-0.52 mg/kg] and are potent noncompetitive gamma-aminobutyric acid (GABA) antagonists. 4-Alkylmonocyclophosphates of the type R1(HOCH2)C(CH2O)2P(O)R2 (where R2 is O-p-nitrophenyl, O-phenyl, S-ethyl, or S-n-propyl) are potential prodrugs by virtue of their cyclization to bicyclophosphates; thus, they may be considered as probicyclophosphates. Both the O-aryl and S-alkyl compounds cyclize via intramolecular transesterification in aqueous medium at pH 7.4 and the S-alkyl derivatives also on oxidation with m-chloroperoxybenzoic acid in chloroform and possibly with microsomal oxidases. For the isomeric O-nitrophenyl, 4-isopropyl compounds, one is equitoxic with the corresponding bicyclophosphate on ip administration to mice while the other is of very low toxicity, a result paralleled by their relative cyclization rates [k(min-1) 4 X 10(-2) and less than 4 X 10(-5), respectively]. The S-alkyl compounds are of intermediate toxicity and the O-phenyl compound is of low toxicity to mice, apparently due to less efficient conversion to the bicyclophosphates. The probable mode of action of these monocyclophosphates as potential prodrugs for bicyclophosphate GABA antagonists is further supported by receptor inhibition studies and identification of the bicyclophosphate products in enzyme systems and in the urine of treated rats.
mesh_terms: D000818:Animals; D001711:Biotransformation; D001643:Bridged Bicyclo Compounds / Q000378:metabolism* / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D003500:Cyclization; D004951:Esterification; D005260:Female; D018756:GABA Antagonists; D006793:Houseflies; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; C041598:t-butylbicyclophosphorothionate receptor