ABSTRACT
The inhibition of the specific R-[3H]-baclofen binding to GABAB (gamma-aminobutyric acid) sites by a homologous series of phenyl alcohol amides was tested in rat brain synaptic membranes. Some of these phenyl alcohol amides were designed as anticonvulsants as well as antagonists of the GABAB receptor. These anticonvulsants showed a high affinity to the GABAB receptor. DL-2-hydroxy-2-(4'-chlorophenyl)butyramide and DL-3-hydroxy-3-(4'-chlorophenyl)pentanamide (DL-Cl-HEPP) were as effective as GABA and R-baclofen and were the most potent examined. DL-2-hydroxy-2-phenylbutyramide (DL-HEPA), (+)-HEPA, (-)-HEPA, DL-3-hydroxy-3-phenylpentanamide (DL-HEPP) and DL-4-hydroxy-4-phenylhexanamide (DL-HEPB) were as potent as DL-baclofen. The phenyl alcohol amides with fluorine in the para position of the phenyl ring were less active than DL-2-hydroxysaclofen. DL-4-hydroxy-4-(4'-chlorophenyl)hexanamide was the least active of the series. In addition, R-baclofen antagonized very effectively the anticonvulsant activity of both DL-HEPP and DL-Cl-HEPP in a dose-dependent fashion. These results support the assumption that some of these phenyl alcohol amides anticonvulsants are GABAB receptor blockers.
Subject(s)
Amides/pharmacology , Anticonvulsants/pharmacology , Baclofen/metabolism , Brain/drug effects , GABA Agonists/metabolism , GABA-B Receptor Antagonists , Synaptic Membranes/metabolism , Amides/chemistry , Animals , Anticonvulsants/chemistry , Brain/metabolism , Brain/ultrastructure , In Vitro Techniques , Male , Mice , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The anticonvulsant activity of a homologous series of p-chlorophenyl alcohol amides is described. The new compounds (+/-)-2-hydroxy-2-(4'-chlorophenyl)-butyramide (2), (+/-)-3- hydroxy-3-(4'-chlorophenyl)pentanamide (4) and (+/-)-4-hydroxy-4-(4'-chlorophenyl)-hexanamide (6), were prepared and tested for their anticonvulsant activity. Compounds 2, 4, and 6 exhibited significant activity in seizures provoked by pentylenetetrazol. Chlorine in the para position of the phenyl ring increased both their potency at the peak effect and the duration of their anticonvulsant activity. The anticonvulsant activities of (+/-)-3-hydroxy-3-phenylpentanamide (3) and compound 4 were antagonized by DL-baclofen. This, and the protecting activity of 3 in the genetic-absence-epilepsy rats of the Strasbourg model suggest that the phenyl alcohol amides could be GABAB receptor antagonists.
Subject(s)
Amides/chemical synthesis , Anticonvulsants/chemical synthesis , GABA-B Receptor Antagonists , Amides/chemistry , Amides/pharmacology , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Baclofen/pharmacology , Convulsants/toxicity , Injections, Intraperitoneal , Magnetic Resonance Spectroscopy , Male , Mice , Pentylenetetrazole/toxicity , Seizures/chemically induced , Seizures/prevention & control , Structure-Activity RelationshipABSTRACT
The anticonvulsant activity of a homologous series of (+/-)-p-fluoro-phenyl alcohol amides is described. The compounds (+/-)-2-hydroxy-2-(4'-fluorophenyl)butyramide (2), (+/-)-3-hydroxy-3-(4'-fluorophenyl)pentanamide (4) and (+/-)-4-hydroxy-4-(4'-fluorophenyl)hexanamide (6) were prepared and tested. Compounds 2, 4 and 6 exhibited a similar significant activity in seizures provoked by pentylenetetrazol. Incorporation of fluorine in the para position of the phenyl ring, increased both their potency at the time of the peak drug effect and the duration of their anticonvulsant activity.
Subject(s)
Anticonvulsants/chemical synthesis , Butyrates/chemical synthesis , Caproates/chemical synthesis , Pentanoic Acids/chemical synthesis , Amides , Animals , Anticonvulsants/pharmacology , Butyrates/pharmacology , Caproates/pharmacology , Convulsants/pharmacology , Injections, Intraperitoneal , Male , Mice , Pentanoic Acids/pharmacology , Pentylenetetrazole/antagonists & inhibitors , Pentylenetetrazole/pharmacology , Seizures/chemically induced , Seizures/prevention & control , Structure-Activity RelationshipABSTRACT
The enantiomers of the anticonvulsant DL-2-hydroxy-2-phenylbutyramide (1) were prepared by resolving the (-)-quinine and (+)-1-phenylethylamine salts of the acids. The optically active acids were then esterified and reacted with ammonia to give (+)-1 and (-)-1. Optical purity of the amides was greater than 99.9% enantiomeric excess by chiral HPLC. Examination of the infrared spectra of the enantiomers and the racemate of 1 in chloroform solution showed identical spectra, but the spectrum of the racemate in a KBr disc was somewhat different from those of the pure enantiomers. Pharmacologically, 1 and its enantiomers have a similar significant anticonvulsant activity at peak drug effect against pentylenetetrazol seizures, but a variation in time between the enantiomers was found with the anticonvulsant activity. In the rotarod ataxia test (-)-1-possessed the lowest neurotoxicity.
Subject(s)
Anticonvulsants/pharmacology , Phenylbutyrates/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/toxicity , Chromatography, High Pressure Liquid , Male , Mice , Pentylenetetrazole , Phenylbutyrates/chemical synthesis , Phenylbutyrates/toxicity , Postural Balance/drug effects , Seizures/chemically induced , Seizures/prevention & control , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , StereoisomerismABSTRACT
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.