Investigation into new anticonvulsant derivatives of alpha-substituted N-benzylamides of gamma-hydroxy- and gamma-acetoxybutyric acid. Part 5: search for new anticonvulsant compounds.
A series of four N-benzylamides of gamma-hydroxybutyric acid (GHB), that contain N-(4-phenylpiperazine)-, N-(4-benzylpiperazine)rings, N-benzylamino-, or N-(2-phenylethylamine)-groups in the alpha-position of GHB were selected as model compounds, for determining the structural elements responsible for their potential anticonvulsant action. Based on the results of pharmacological, physicochemical, and molecular modelling investigations, the pharmacophore model for anticonvulsant N-substituted amides of GHB was defined. In this model, the presence of the N-benzylamide fragment is essential for activity. In addition, all of the amides contained another hydrophobic unit (aryl ring) as a distal binding site and H-bond donor. In consideration of these model parameters, a number of N-substituted amides of GHB, containing a hydrophobic moiety such as: N-benzylamino or N-(4-chlorobenzylamino) group in the alpha-position of GHB, and a lipophilic substituent in the amide portion, were prepared. It has been shown that the anticonvulsant activities of the newly synthesized compounds might partially be explained on the basis of their lipophilicity (calculated log P values) and the presence of a hydroxyl group in the molecule.
Malawska
Barbara
B
Department of Pharmaceutical Chemistry, Medical College of Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland. mfmalaws@cyf-kr.edu.pl
Kulig
Katarzyna
K
Spiewak
Agnieszka
A
Stables
James P
JP
D000577:Amides / Q000737:chemistry; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020148:Butyric Acid / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D006900:Hydroxylation; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D000927:Anticonvulsants; D020148:Butyric Acid