A novel antagonist, phenylbenzene omega-phosphono-alpha-amino acid, for strychnine-sensitive glycine receptors in the rat spinal cord.
1. 3-[2'-Phosphonomethyl[1,1'-biphenyl]-3-yl]alanine (PMBA) is a novel glycine antagonist at strychnine-sensitive receptors. The chemical structure of PMBA, possessing both a glycine moiety and a phosphono group, is quite different from that of strychnine. 2. In the spinal motoneurone of newborn rats, glycine (100 microM-1 mM) induced depolarizing responses in a concentration-dependent manner. PMBA effectively inhibited depolarizing responses to glycine and other agonists, such as taurine and beta-alanine. The dose-response curves for glycine were shifted to the right in an almost parallel manner (pA2 value: 5.30 +/- 0.23, n = 5) by PMBA which was about 60 times less potent than strychnine (pA2 value: 7.08 +/- 0.21, n = 5) as a glycine antagonist. 3. PMBA (1-100 microM) did not interact with modulatory glycine sites on N-methyl-D-aspartate (NMDA) receptors, which suggests a high selectivity of PMBA for strychnine-sensitive glycine receptors. At considerably high concentrations (0.1 mM-1 mM), PMBA depressed responses to GABA (pA2 value: 3.57 +/- 0.24, n = 3). 4. PMBA inhibited the binding of [3H]-strychnine to synaptosomes from adult rat spinal cords; the IC50 values of PMBA, glycine and strychnine were 8 +/- 2, 9 +/- 3 and 0.08 +/- 0.04 microM, respectively (n = 5) for [3H]-strychnine (4.8 nM). 5. PMBA is a central excitant drug with relatively high potency and selectivity and should be useful as a pharmacological probe for analysing the mechanisms underlying physiological functions of glycine receptors.
Saitoh
T
T
Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Japan.
Ishida
M
M
Maruyama
M
M
Shinozaki
H
H
D000818:Animals; D000831:Animals, Newborn; D004594:Electrophysiology; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000037:antagonists & inhibitors; D018377:Neurotransmitter Agents / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
C091378:3-(2'-phosphonomethyl(1,1'-biphenyl)-3-yl)alanine; D018756:GABA Antagonists; D018377:Neurotransmitter Agents; D063065:Organophosphonates; D018009:Receptors, Glycine; D010649:Phenylalanine; D013331:Strychnine; D005998:Glycine