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Heteromeric metabotropic γ-aminobutyric acidB (GABAB) receptors for the inhibitory neurotransmitter GABA belong to the family 3 of G-protein-coupled receptors, together with metabotropic glutamate receptors, extracellular Ca2+-sensing receptors and some pheromone and taste receptors. It is now generally appreciated that allosteric modulators provide a new perspective for the development of subtype-selective agents acting at G-protein-coupled receptors. Such modulators interact with allosteric binding sites quite separate from the highly conserved agonist binding region, providing a variety of potential modulatory actions. Allosteric interaction modifies the binding affinity of the agonist, and is a commonly found mechanism governing receptor function. The GABAB receptor itself is unique, as its function depends on heterodimerization of two subunits, GABAB1 and GABAB2. Only GABAB1 has the orthosteric binding region, whereas GABAB2 does not bind agonists or antagonists, but is modulatory for GABAB1. GABAB2 is also the signaling subunit for G-protein activation; yet no agonist is known. We have found a range of arylalkylamines and unnatural amino-acids that are effective positive modulators of GABAB receptors. These new modulators proposed at GABAB receptors may well have novel applications in GABAB receptor pharmacology.