ABSTRACT
New N-heteroarylcarbonylalanines of the D-series were stereoselectively prepared from enoates derived from D-mannitol. These compounds were active in binding and functional assays of the NMDA sub-type of glutamate receptors. A pyridine derivative inhibited MK801 binding, protected neurons from excitotoxic damage and blocked NMDA-induced currents in neurons. A thiophene derivative positively modulated the NMDA receptor, possibly through the allosteric glycine site.
Subject(s)
Alanine/chemical synthesis , Alanine/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Cerebral Cortex/metabolism , Dizocilpine Maleate/metabolism , Drug Evaluation, Preclinical/methods , Ligands , Protein Binding/physiology , Rats , Rats, Wistar , Stereoisomerism , Thiophenes/chemical synthesis , Thiophenes/metabolismABSTRACT
Research aimed at developing selective drugs acting on gamma-aminobutyric acid (GABA)A receptors introduced compounds from diverse chemical classes unrelated to the 1,4-benzodiazepines, including flavonoids. These studies also revealed the potential use of inverse agonists as cognition-enhancing agents. Here we report pharmacological properties of the novel synthetic isoflavonoid 2-methoxy-3,8,9-trihydroxy coumestan (PCALC36). PCALC36 displaced [3H]flunitrazepam binding to rat brain synaptosomes with an IC50 of 13.8 microM. Scatchard analysis of the effect of PCALC36 showed a concentration-dependent reduction of the Bmax of [3H]flunitrazepam, without a marked change in Kd. This effect could be reversed by diluting and washing the preparation. Addition of 20-microM GABA shifted to the right the inhibition curve of PCALC36 on [3H]flunitrazepam binding (IC50 ratio of 0.68), which is characteristic for inverse agonists. PCALC36 produced little change in the GABAergic tonic currents recorded by whole-cell patch clamp in cultured rat hippocampal neurones, but it caused a 20% reduction in miniature inhibitory postsynaptic current amplitude and completely antagonised the full (direct) agonist midazolam in a quickly reversible manner. The data suggest that the coumestan backbone can be useful for developing novel ligands at the GABAA receptor.
Subject(s)
Flavonoids/pharmacology , GABA Agonists/pharmacology , GABA-A Receptor Agonists , Isoflavones/pharmacology , Analysis of Variance , Animals , Bicuculline/pharmacology , Binding, Competitive/drug effects , Brain/metabolism , Dose-Response Relationship, Drug , Female , Flavonoids/chemical synthesis , Flunitrazepam/metabolism , GABA Agonists/chemical synthesis , GABA Modulators/pharmacology , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/physiology , Isoflavones/chemical synthesis , Isoflavones/metabolism , Kinetics , Male , Membrane Potentials/drug effects , Midazolam/pharmacology , Neurons/drug effects , Neurons/physiology , Pregnancy , Rats , Rats, Wistar , Receptors, GABA-A/physiology , Synaptosomes/metabolism , Time Factors , Tritium , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Seven new 1,4-naphthoquinones structurally related to lapachol were synthesized from lawsone and oxygenated arylmercurials. These compounds can also be seen as pterocarpan derivatives where the A-ring was substituted by the 1,4-naphthoquinone nucleus. Pharmacological screening provided evidence of significant biological activities, including effects against proliferation of the MCF-7 human breast cancer cell line, against Herpes Simplex Virus type 2 infection, and against snake poison-induced myotoxicity. One derivative displaced flunitrazepam binding and showed benzodiazepine-like activity, suggesting novel neuroactive structural motifs.
