N-Substituted 4-amino-3,3-dipropyl-2(3H)-furanones: new positive allosteric modulators of the GABA(A) receptor sharing electrophysiological properties with the anticonvulsant loreclezole.
1,4-Addition of benzylamine to 2(5H)-furanone followed by dialkylation of the 3-position with allylbromide gave (+/-)-4-benzyl-3,3-diallyl-2(3H)-furanone (8), which served as the intermediate for the synthesis of various N-substituted 4-amino-3,3-dipropyl-2(3H)-furanones (+/-)-9a-l. The compounds were evaluated for their capacity to potentiate or inhibit GABA-evoked currents in Xenopus laevis oocytes expressing recombinant alpha1beta2gamma2 GABA(A) receptors. The benzyl, ethyl, and allyl carbamates ((R)-9a (100 microM), (+/-)-9b (100 microM), (+/-)-9c (200 microM)) stimulated GABA currents by 279 +/- 47%, 426 +/- 8%. and 765 +/- 61%, respectively, while the phenylcarboxamide (+/-)-9f (200 microM) stimulated currents by 420 +/- 33%. Concentration-response studies showed that compound 9c was approximately twice as potent in stimulating GABA currents as alpha-EMTBL (2), the most potent 3,3-dialkylbutyrolactone known to date. On the other hand, the N-sulfonyl analogues were much less active or even inhibited GABA-evoked currents. In vitro radioligand displacement studies on rat brain membranes showed that these compounds did not bind to the benzodiazepine or GABA recognition sites of the GABA(A) receptor. However, these compounds generally weakly displaced [(35)S]-TBPS (approximately 50% displacement at 100 microM), though potencies did not correlate with GABA current potentiation. Results obtained with alpha1beta1 and mutant alpha1beta2N265S receptors, which compared to alpha1beta2 receptors are both much less sensitive to current stimulation produced by the anticonvulsant loreclezole, suggest that at least some of these aminobutyrolactones, (e.g., 9a, 9c), and interestingly also alpha-EMTBL, share stimulatory properties with loreclezole.
El Hadri
Ahmed
A
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette Cedex, France.
Abouabdellah
Ahmed
A
Thomet
Urs
U
Baur
Roland
R
Furtmüller
Roman
R
Sigel
Erwin
E
Sieghart
Werner
W
Dodd
Robert H
RH
D000494:Allosteric Regulation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004560:Electricity; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology; D014982:Xenopus laevis
D000927:Anticonvulsants; D005663:Furans; D007783:Lactones; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D014230:Triazoles; C066440:loreclezole