Subject(s)
Humans , Fatty Acids/pharmacology , Globins/genetics , Phenylbutyrates/pharmacology , Cells, Cultured , Erythroid Precursor Cells/drug effects , Erythroid Precursor Cells/metabolism , Fatty Acids/chemistry , Fetal Hemoglobin/biosynthesis , Hemoglobinopathies/blood , Hemoglobinopathies/drug therapy , Hemoglobinopathies/genetics , Leukemia, Erythroblastic, Acute , Phenylacetates/pharmacology , Phenylbutyrates/chemistry , Promoter Regions, Genetic/drug effects , Structure-Activity Relationship , Tumor Cells, Cultured , Up-Regulation/drug effectsABSTRACT
The anticonvulsant activity of a homologous series of phenyl alcohol amides is described. (+-)-2-Hydroxy-2-phenylbutyramide (1), (+-)-3-hydroxy-3-phenylpentanamide (2) and (+-)-4-hydroxy-4-phenylhexanamide (3) were prepared and tested for their anticonvulsant profile and neurotoxicity. 1, 2 and 3 exhibited a broad profile of anticonvulsant activity and a similar significant activity in the seizures provoked by maximal electroshock, pentetrazol, 4-aminopyridine, bicuculline and thiosemicarbazide, but in the strychnine and picrotoxin tests, the protection was variable. The rotarod ataxia test was used to evaluate their neurotoxicity. In this test 2 possesses the lowest neurotoxicity.
Subject(s)
Amides/chemical synthesis , Anticonvulsants/chemical synthesis , Hydroxy Acids/chemical synthesis , Phenylbutyrates/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Electroshock , Hydroxy Acids/chemistry , Hydroxy Acids/pharmacology , Male , Mice , Phenylbutyrates/chemistry , Phenylbutyrates/pharmacology , Postural Balance/drug effects , Seizures/chemically induced , Seizures/prevention & controlABSTRACT
The partition coefficients of three homologous anticonvulsant phenylalkylamides [racemic alpha-hydroxy-alpha-ethyl-alpha-phenylacetamide (HEPA); beta-hydroxy-beta-ethyl-beta-phenylpropionamide (HEPP); and gamma-hydroxy-gamma-ethyl-gamma-phenylbutyramide (HEPB)] were determined by reversed-phase high-performance liquid chromatography (RP-HPLC). The system was calibrated with a series of simple amines and amides, using their published log P values. The log kw values (methanol:water, extrapolated to 100% water) were 1.260 for HEPA, 1.670 for HEPP, and 1.852 for HEPB. From these results, the partition coefficients (log P) were calculated by regression as 1.20, 1.83, and 2.11, respectively. The log P values were essentially equal to those calculated by the Leo-Hansch fragmental method. Since the potency of the three anticonvulsants is approximately the same in a variety of tests, no dependence on lipophilicity could be established.