The GABA receptor affinity of a number of GABA analogues, where the carboxylic acid group has been replaced with a range of acidic moieties, were determined. The phosphinic acid analogue (1) was identified as a potent selective GABA ligand which is CNS penetrating and 10-fold more active than baclofen (2). The amino acid GABA (3) is the major inhibitory neurotransmitter in the mammalian central nervous system. Receptors for GABA are subdivided into GABAₐ and GABAᵦ. The GABAₐ receptors (the classical GABA receptor) has been exploited therapeutically in the benzodiazepine anxiolytics which modulate it. Evidence for the GABAᵦ receptor was first described by Bowery and colleagues in the early eighties, but there is still a dearth of appropriate chemical tools. The only selective potent GABAᵦ agonists are baclofen (2) and the recently introduced phosphonous acid, CGP 27492 (4). Until recently there were no potent GABAᵦ antagonists described, only a number of weak compounds which include phaclofen (5), saclofen (6), 2-hydroxysaclofen (7) and a series of phosphinic acids represented by CGP 35348 (8). Further studies around compounds such as 8 have led Frijstl et al to describe a series of new potent GABAᵦ antagonists exemplified by CGP 52432. Our interest in this field, prompted us to undertake a SAR study concerning bioisosteric replacements for the carboxylic acid moiety in GABA, as GABAᵦ ligands. This led to the discovery of 3-aminopropyl(methyl)phosphinic acid, SK&F 97541 (1) as the most potent, selective GABAᵦ agonist to date. Here we describe the biological activity of this compound, and a comparison with the GABA binding affinity of other GABA analogues where the carboxylic acid has been replaced (Table I). The phosphinic acids 1, 9, 10, the phosphonous acid 4, and the (diethoxymethyl)phosphinic acid 8 were prepared by the methods of Howson, Dingwall and Bayliss respectively. Using an in vitro binding assay (displacement of [³H]-GABA from GABAᵦ sites in rat brain membranes) the affinity of the compounds were assessed: the results are shown in Table I. This led to the following conclusions concerning structure and affinity. The compounds GABA (3) and baclofen (2), which possess the planar carboxylic acid functionality where the charge is spread over just two heteroatoms, were shown to have affinities in the 0.1 - 0.01 µM range for the GABAᵦ receptor. All compounds which have an acidic moiety where the charge is spread over more than two heteroatoms have significantly weaker affinity. These include derivatives with distorted tetrahedral acidic groups i.e. 11-14, and the planar monocharged tetrazole GABA analogue. If the acidic moiety is a singly charged distorted tetrahedral group, with the charge spread over just two oxygen atoms, such as in 1 and 4, high affinity agonists for the GABAᵦ receptor are obtained. Increasing the size of the alkyl substituent on the phosphorus atom affords weakly active antagonists (8, 9, 10) at GABAᵦ receptors. The phosphinic acid 1 was subsequently shown to be highly selective for the GABAᵦ receptor vs the GABAₐ receptor, binding to the GABAᵦ receptor with IC₅₀ = 0.001 µM and to the GABAₐ receptor with IC₅₀ > 100 µM, a selectivity ratio of 10⁵. Its agonist activity on a number of in vitro peripheral GABAᵦ receptor assays (guinea-pig ileum, rat vas deferens and anococcygeus) was invariably an order of magnitude greater than baclofen, but similar to the phosphonous acid 4. While in two in vitro CNS GABAᵦ preparations (rat substantia nigra and striatum slices) differences between 1 and 4 were observed. Here, 1 was ten times more potent than 4 and 4 was equipotent or less potent than baclofen, 4 also showed partial agonist activity. Further studies have shown the major difference between the two acids 1 and 4 is their apparent ability to penetrate the CNS. Hypothermia in the mouse is known to be a feature of the central action of baclofen. In studies comparing the hypothermic effects of 1 and 4 with baclofen, it was found that 1 (0.1 - 1 mg/Kg i.p.) and baclofen (1 - 10 mg/Kg i.p.) caused a marked and dose related decrease in body temperature. While 4, studied at doses up to 5 mg/Kg i.p. was without effect on mouse body temperature. All of the agonist effects of the phosphinic acid 1 described above could be antagonised by the hexyl analogue 10. In summary, the affinity of a number of GABA analogues where the acidic group has been replaced have been studied. This led to the identification of the phosphinic acid 1, a potent selective GABA ligand which is CNS penetrating and some ten-fold more active than baclofen.