Actions of cyclic esters, S-esters, and amides of phenyl- and phenylthiophosphonic acids on mammalian and insect GABA-gated chloride channels.
Cyclic esters, S-esters, and amides of phenyl(thio)phosphonic acid were synthesized to probe the interaction between noncompetitive antagonists of ionotropic gamma-aminobutyric acid (GABA) receptors and their binding site. Some of these compounds competitively inhibited the specific binding of [3H]EBOB, a noncompetitive GABA antagonist, to rat-brain 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-position (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 potent. The potencies of 5t and 12t tended to decrease in the presence of GABA, particularly in housefly receptors, while that of 10t remained unchanged. The rank order of activity in inhibiting [3H]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 microM and 300 microM GABA-induced 36Cl- influx into mouse cerebral synaptoneurosomes, whereas ester 5t depressed 10 microM GABA-induced 36Cl- influx but not 300 microM GABA-induced flux. Amide 12t was inactive at both GABA concentrations. These findings indicate that six-membered cyclic phenylthiophosphonic acid derivatives act as noncompetitive antagonists of GABA receptors and suggest that 10t is able to bind to the receptor in the open, desensitized, and closed states, whereas the affinity of 5t and 12t is lower in the open and desensitized states than 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 GABA-gated channel to the desensitized or closed state.
Ozoe
Y
Y
Department of Life Science and Biotechnology, Shimane University, Matsue, Japan. ozoe-y@life.shimane-u.ac.jp
Niina
K
K
Matsumoto
K
K
Ikeda
I
I
Mochida
K
K
Ogawa
C
C
Matsuno
A
A
Miki
M
M
Yanagi
K
K
D000345:Affinity Labels; D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000648:ultrastructure; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D018756:GABA Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006793:Houseflies; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000648:ultrastructure
D000345:Affinity Labels; D000577:Amides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D004952:Esters; D018756:GABA Antagonists; D007306:Insecticides; D063065:Organophosphonates; D018079:Receptors, GABA; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane