ACTIONS OF CYCLIC ESTERS, S-ESTERS, AND AMIDES OF PHENYLPHOSPHONIC AND PHENYLTHIOPHOSPHONIC ACIDS ON MAMMALIAN AND INSECT GABA-GATED CHLORIDE CHANNELS

Cyclic esters, S-esters, and amides of phenyl(thio)phosphonic acid wer e synthesized to probe the interaction between noncompetitive antagoni sts of ionotropic gamma-aminobutyric acid (GABA) receptors and their b inding site. Some of these compounds competitively inhibited the speci fic binding of [H-3]EBOB, a noncompetitive GABA antagonist, to rat-bra in and housefly-head membranes. The trans isomer of the ester bearing a tert-butyl group at the 5-position and a bromine atom at the p-posit ion (5t) was most potent in rat receptors with an IC50 value of 40 nM, while the trans isomer of the S-ester bearing the same substituents ( 10t) was most potent in housefly receptors with an IC50 value of 55 nM . In both cases, the corresponding amide analogue (12t) was less poten t. The potencies of 5t and 12t tended to decrease in the presence of G ABA, particularly in housefly receptors, while that of 10t remained un changed. The rank order of activity in inhibiting [H-3]EBOB binding to housefly-head membranes in the presence of GABA (10t > 5t > 12t) was in accord with that of insecticidal activity. S-Ester 10t depressed 10 mu M and 300 mu M GABA-induced Cl-36(-) influx into mouse cerebral sy naptoneurosomes, whereas ester 5t depressed 10 mu M GABA-induced Cl-36 (-) influx but not 300 mu M GABA;induced flux. Amide 12t was inactive at both GABA concentrations. These findings indicate that six-membered cyclic phenylthiophosphonic acid derivatives act as noncompetitive an tagonists of GABA receptors and suggest that 10t is able to bind to th e receptor in the open, desensitized, and closed states, whereas the a ffinity of 5t and 12t is lower in the open and desensitized states tha n in the closed state. The derivatives have similar structures except for the heteroatoms at the 1- and 3-positions, so that the heteroatoms may play a unique role when antagonists bring the open state of the G ABA-gated channel to the desensitized or closed state. (C) 1998 Elsevi er Science Ltd. All rights reserved.