title: Interactions of taurine and structurally related analogues with the GABAergic system and taurine binding sites of rabbit brain.
abstract: 1. The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. 2. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [(3)H]muscimol. Saturation experiments of the binding of [(3)H]GABA to GABA(B) receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [(3)H]taurine in a saturable manner (K(d)=249.0+/-6.3 nM and B(max)=3.4+/-1.0 pmol mg(-1) prot). 3. Among the 19 structural analogues of taurine, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (+/-)cis-2-aminocyclohexane sulfonic acids (CAHS) displaced [(3)H]taurine binding (K(i)=0.13, 0.13, 13.5 and 4.0 micro M, respectively). These analogues did not interact with GABA(A) and GABA(B) receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 4. 3-Aminopropanesulfonic acid (OMO), beta-alanine, pyridine-3-sulfonic acid, N,N,N-trimethyltaurine (TMT), 2-(guanidino)ethanesulfonic acid (GES), ethanolamine-O-sulphate, N,N-dimethyltaurine (DMT), taurine and (+/-)piperidine-3-sulfonic acid (PSA) inhibited [(3)H]muscimol binding to GABA(A) receptors with different affinities (K(i)=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 micro M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [(3)H]GABA to GABA(B) receptors with K(i)'s in the micro M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC(50)=3.72 micro M) and PSA GABA transaminase activity (IC(50)=103.0 micro M). 5. In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents.
authors.affiliation: Istituto di Scienze Farmacologiche, Universita di Siena, Viale A Moro 2, lotto C, 53100 Siena, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.forename: Casilde
authors.initials: C
authors.lastname: Sesti
authors.forename: Stefania
authors.initials: S
authors.lastname: Dragoni
authors.forename: Massimo
authors.initials: M
authors.lastname: Valoti
authors.forename: Mitri
authors.initials: M
authors.lastname: Palmi
authors.forename: Henry B F
authors.initials: HB
authors.lastname: Dixon
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Machetti
authors.forename: Giampietro
authors.initials: G
authors.lastname: Sgaragli
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D004347:Drug Interactions; D007536:Isomerism; D015394:Molecular Structure; D009118:Muscimol / Q000493:pharmacokinetics; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000737:chemistry; D013574:Synaptosomes / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics*
chemical_list: D010880:Piperidines; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D017981:Receptors, Neurotransmitter; C030803:taurine receptor; D014316:Tritium; D013654:Taurine; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; C032727:piperidine; D000612:4-Aminobutyrate Transaminase