Interactions of taurine and structurally related analogues with the GABAergic system and taurine binding sites of rabbit brain

• Published in: British journal of pharmacology Vol. 138; no. 6; pp. 1163 - 1171
• Main Authors: Frosini, Maria, Sesti, Casilde, Dragoni, Stefania, Valoti, Massimo, Palmi, Mitri, Dixon, Henry B F, Machetti, Fabrizio, Sgaragli, Giampietro
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2003; Nature Publishing
• Subjects: 4-Aminobutyrate Transaminase - antagonists & inhibitors; 4-Aminobutyrate Transaminase - metabolism; Animals; Binding Sites - physiology; Biological and medical sciences; Brain - metabolism; Drug Interactions; GABA; GABA receptors; gamma-Aminobutyric Acid - pharmacokinetics; Isomerism; Medical sciences; Molecular Structure; Muscimol - pharmacokinetics; Piperidines - metabolism; Piperidines - pharmacology; Rabbits; Receptors, GABA-A - metabolism; Receptors, GABA-B - metabolism; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; Structure-Activity Relationship; Synaptic Membranes - chemistry; Synaptosomes - metabolism; Taurine; Taurine - analogs & derivatives; Taurine - chemical synthesis; Taurine - pharmacokinetics; taurine binding site; taurine derivatives; Tritium; GABA; Taurine; taurine binding site; taurine derivatives; GABA receptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705134

The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems.
Washed synaptic membranes (SM) from whole rabbit brain were able to bind [3H]muscimol. Saturation experiments of the binding of [3H]GABA to GABAB receptors showed that SM possess two binding components; twice Triton X‐100‐treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [3H]taurine in a saturable manner (Kd=249.0±6.3 nM and Bmax=3.4±1.0 pmol mg−1 prot).
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 [3H]taurine binding (Ki=0.13, 0.13, 13.5 and 4.0 μM, respectively). These analogues did not interact with GABAA and GABAB receptors and did not affect taurine‐ and GABA‐uptake systems and GABA‐transaminase activity.
3‐Aminopropanesulfonic acid (OMO), β‐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 [3H]muscimol binding to GABAA receptors with different affinities (Ki=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 μM, respectively). Taurine, 2‐aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [3H]GABA to GABAB receptors with Ki's in the μM range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC50=3.72 μM) and PSA GABA transaminase activity (IC50=103.0 μM).
In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents.
British Journal of Pharmacology (2003) 138, 1163–1171. doi:10.1038/sj.bjp.0705134