5-[4-(3,3-Dimethylbutoxycarbonyl)phenyl]-4-pentynoic acid and its derivatives inhibit ionotropic gamma-aminobutyric acid receptors by binding to the 4 '-ethynyl-4-n-propylbicycloorthobenzoate site

Citation
H. Hamano et al., 5-[4-(3,3-Dimethylbutoxycarbonyl)phenyl]-4-pentynoic acid and its derivatives inhibit ionotropic gamma-aminobutyric acid receptors by binding to the 4 '-ethynyl-4-n-propylbicycloorthobenzoate site, BIO MED CH, 8(3), 2000, pp. 665-674
Citations number
20
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN journal
09680896 → ACNP
Volume
8
Issue
3
Year of publication
2000
Pages
665 - 674
Database
ISI
SICI code
0968-0896(200003)8:3<665:5AAID>2.0.ZU;2-P
Abstract
Acyclic noncompetitive antagonists of ionotropic gamma-aminobutyric acid (G ABA) receptors, bearing an ester or ether linkage, were designed, synthesiz ed, and assayed for their inhibition of the specific binding of [H-3]4'-eth ynyl-4-n-propylbicycloorthobenzoate (EBOB), a radiolabeled noncompetitive a ntagonist, to rat brain and housefly head membranes. 5-[4-(3,3-Dimethylbuto xycarbonyl)phenyl]-4-pentynoic acid (DBCPP), a butyl benzoate analogue, was found to competitively inhibit the binding of [H-3]EBOB in rat brain membr anes, with an IC50 of 88 nM. The potency conferred by the p-substituent dec reased in the order C=C(CH2)(2)COOH > C=C(CH2)(2)COOCH3 > C=CH > Br. Pentyl phenyl ethers were equally potent compared with butyl benzoates, while phe nyl pentanoates and benzyl butyl ethers were less potent. These compounds w ere generally less active in housefly head membranes than in rat brain memb ranes. The introduction of an isopropyl group into the 1-position of the 3, 3-dimethylbutyl group of a butyl benzoate and two benzyl butyl ethers cause d an increase in potency in housefly GABA receptors, whereas this modificat ion at the corresponding position of other compounds led to an unchanged or decreased potency. In the case of rat receptors, this modification resulte d in a decrease in potency except for a phenyl pentanoate. To confirm that DBCPP interferes with GABA receptor function, we performed whole-cell patch clamp experiments with rat dorsal root ganglion neurons in the primary cul ture. Repeated co-applications of GABA and DBCPP suppressed GABA-induced wh ole-cell currents with an IC50 Of 0.54 mu M and a Hill coefficient of 0.7. These findings indicate that DBCPP and its derivatives inhibit ionotropic G ABA receptors by binding to the EBOB site and that there might be structura l difference in the noncompetitive antagonist-binding site between rat and housefly GABA receptors. (C) 2000 Elsevier Science Ltd. All rights reserved .