Ligands for the isolation of GABAB receptors : W. Froestl would like to dedicate this work to the first GABAB chemist, Cr Heinrich Keberle, on the occasion of his 77th birthday

Since the discovery that the most abundant inhibitory neurotransmitter in the mammalian brain, GABA (g-aminobutyric acid), interacts not only with ionotropic GABAA receptors, but also with metabotropic GABAB receptors (Bowery et al., 1980) much work has been devoted to the elucidation of the structure of GABAB receptors by either affinity chromatography purification or by expression cloning. In 1997 Kaupmann et al. succeeded in cloning two splice variants designated GABAB R1a (960 amino acids) and GABAB R1b (844 amino acids). Although the amino acid sequences are now known, precise information on the three-dimensional environment of the GABAB R1 binding site is still lacking. Recent experiments demonstrated that the amino acids of the seven transmembrane helices are not essential for ligand binding as a soluble GABAB receptor fragment is still able to bind antagonists (Malitschek et al., 1999). For the isolation and purification of the soluble N-terminal extracellular domain (NTED) of GABAB receptors potent ligands for affinity chromatography were synthesised with the aim of obtaining a crystalline receptor fragment-ligand complex for X-ray structure determination. The most promising ligand [ 125 I]CGP84963 (KD2 nM) combines, in one molecule, a GABAB receptor binding part, an azidosalicylic acid as a photoaffinity moiety separated by a spacer consisting of three GABA molecules from 2-iminobiotin, which binds to avidin in a reversible, pH-dependent fashion. © 1999 Elsevier Science Ltd. All rights reserved.