ABSTRACT
A series of potential anticonvulsants have been synthesized. There are eight fluorobenzylamides and three chlorobenzylamides of isocyclic or heterocyclic acids. Two not halogenated benzylamides were also synthesized to compare the effect of halogenation. The aim of the research performed was to evaluate whether halogenation of the mother structure is able to improve its anticonvulsant activity. The compounds were tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Compound 1 showed MES ED50 = 80.32 mg/kg, PI = 3.16. Compound 7 showed CKM ED50 = 56.72 mg/kg. Compound 8 showed MES ED50 = 34.23 mg/kg and scPTZ ED50 > 300 mg/kg, PI = 8.53.Compound 13 showed 6Hz ED50 = 78.96, PI = 3.37. The results indicate that fluorination does not improve activity, whereas chlorination in our experiment even reduces it.
Subject(s)
Acids, Heterocyclic/chemical synthesis , Amides/chemical synthesis , Anticonvulsants/chemical synthesis , Benzyl Compounds/chemical synthesis , Acids, Heterocyclic/pharmacology , Amides/pharmacology , Animals , Anticonvulsants/pharmacology , Benzyl Compounds/pharmacology , Mice , Structure-Activity RelationshipABSTRACT
A series of benzylamides of isocyclic and heterocyclic acids was synthesized and tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Near all synthesized derivatives of heterocyclic acids showed activity. All obtained derivatives of mono- and bicyclic isocyclic acids were inactive. The power of action of heterocyclic acids derivatives seems does not depend upon kind of heteroatom (N, O or S). One of the compounds (2-furoic acid benzylamide (4)) appeared most promising. It showed in minimal clonic seizure (6Hz) test (ASP) in rats after i. p. administration: MES ED50 = 36.5 mg/kg, TOX TD50 = 269.75 mg/kg, and PI = 7.39.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Benzyl Compounds/chemical synthesis , Benzyl Compounds/pharmacology , Seizures/prevention & control , Amides/toxicity , Animals , Anticonvulsants/toxicity , Benzyl Compounds/toxicity , Disease Models, Animal , Molecular Structure , Pilocarpine , Rats , Seizures/chemically induced , Structure-Activity RelationshipABSTRACT
Previously obtained picolinic acid benzylamide is a potent anticonvulsant with low neurotoxicity. In search for new effective anticonvulsants twelve new benzylamides (1-12) were synthesized and preliminary evaluated in the Anticonvulsant Screening Program (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Two of them appeared the most promising: 1-cyclopentenecarboxylic acid benzylamide (1-Cpc-BZA) (9) showed MES ED50 = 85,36 mg/kg (PI = 2,49), scPTZ ED50 = 1,37 mg/kg (PI = 1,37), 6Hz-EST ED50 = 50,29 mg/kg and cyclopentanecarboxylic acid benzylamide (Cpc-BZA) (11) showed pilocarpine ED50 = 154.75 mg/kg and pilocarpine ED97 = 270.95 mg/kg.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Animals , Anticonvulsants/toxicity , Benzamides/toxicity , Convulsants , Electroshock , Mice , Muscarinic Agonists/pharmacology , Neurotoxicity Syndromes/psychology , Pentylenetetrazole , Pilocarpine/antagonists & inhibitors , Rats , Seizures/chemically induced , Seizures/drug therapy , Seizures/etiologyABSTRACT
Previously obtained Pic-BZA is a potent anticonvulsant with low neurotoxicity, but its half-time of action is only about 15 min. In search for equally effective anticonvulsants but with a longer time of action fourteen Pic-BZA analogs were obtained. The compounds were evaluated in the Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Picolinic acid 2-fluorobenzylamide (Pic-2-F-BZA, 7) appeared to be the most effective compound of the series.
Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Picolinic Acids/chemistry , Picolinic Acids/pharmacology , Seizures/prevention & control , Animals , Anticonvulsants/chemical synthesis , Computers , Drug Design , Electric Stimulation , Mice , Picolinic Acids/chemical synthesis , Seizures/chemically induced , Structure-Activity RelationshipABSTRACT
A series of new potential anticonvulsants have been synthesized. They are N-methyl benzyl-amides of N-methyl Asp and N-methyl Glu (R and S), benzylamides of some heterocyclic acids and their N-oxides and benzylamides of two heteroalicyclic acids. The obtained compounds were evaluated in the Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH.
