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N-Propynyl analogs of β-phenylethylidenehydrazines: Synthesis and evaluation of effects on glycine, GABA, and monoamine oxidase
- Source :
- Bioorganic & Medicinal Chemistry. 16:8254-8263
- Publication Year :
- 2008
- Publisher :
- Elsevier BV, 2008.
-
Abstract
- A group of beta-phenylethylidenehydrazines possessing a variety of substituents (Me, OMe, Cl, F, and CF(3)) at the ortho-, meta-, or para-positions of the phenyl ring, in conjunction with either a N-bis-(2-propynyl) or a N-mono-(2-propynyl) moiety, were synthesized and compared to the novel neuroprotective drug beta-phenylethylidenehydrazine (PEH) with regard to their ability to inhibit the enzymes GABA-transaminase (GABA-T) and monoamine oxidase (MAO)-A and -B in vitro in brain tissue. Two of the analogs synthesized (mono- and bis-N-propynylPEH) were also studied exvivo in rats to compare their effects to those of PEH with regard to ability to inhibit GABA-T and MAO and to change brain levels of several important amino acids. Unlike PEH, none of the new drugs inhibited GABA-T in vitro at 10 or 100 microM, and all of the drugs (including PEH) were poor inhibitors (at 10 microM) of MAO-A and -B invitro. The two analogs studied exvivo inhibited GABA-T to a lesser extent than PEH, unlike PEH that did not elevate brain levels of GABA, and inhibited MAO-A and -B more potently than PEH. Interestingly, unlike PEH, the two analogs caused marked increases in brain levels of glycine; because of the current interest in drugs that increase glycine availability in the brain as potential antipsychotic drugs, these two analogs now warrant further investigation.
- Subjects :
- Male
Monoamine oxidase
Clinical Biochemistry
Drug Evaluation, Preclinical
Glycine
Pharmaceutical Science
Biochemistry
Chemical synthesis
Rats, Sprague-Dawley
Structure-Activity Relationship
Drug Discovery
Animals
Enzyme Inhibitors
Monoamine Oxidase
Molecular Biology
chemistry.chemical_classification
Molecular Structure
biology
Organic Chemistry
Brain
Stereoisomerism
In vitro
Rats
Amino acid
Enzyme Activation
Hydrazines
Enzyme
chemistry
Enzyme inhibitor
4-Aminobutyrate Transaminase
Alkynes
biology.protein
Molecular Medicine
Ex vivo
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....398e1ccb4b8436a4c89d14c00024321e