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GABA(C) receptors are the least studied of the three major classes of GABA receptors. The physiological roles of GABA(C) receptors are still being unravelled and the pharmacology of these receptors is being developed. A range of agents has been described that act on GABA(C) receptors with varying degrees of specificity as agonists, partial agonists, antagonists and allosteric modulators. Pharmacological differences are known to exist between subtypes of cloned GABA(C) receptors that have been cloned from mammalian sources. There is evidence for functional GABA(C) receptors in the retina, spinal cord, superior colliculus, pituitary and gastrointestinal tract. Given the lower abundance and less widespread distribution of GABA(C) receptors in the CNS compared to GABA(A) receptors, GABA(C) receptors may be a more selective drug target than GABA(A) receptors. The major indications for drugs acting on GABA(C) receptors are in the treatment of visual, sleep and cognitive disorders. The most promising leads are THIP, a GABA(C) receptor antagonist in addition to its well known activity as a GABA(A) receptor partial agonist, which is being evaluated for sleep therapy, and CGP36742, an orally active GABA(B) and GABA(C) receptor antagonist, which enhances cognition. Analogues of THIP and CGP36742, such as aza-THIP, that are selective for GABA(C) receptors are being developed. TPMPA and related compounds such as P4MPA, PPA and SEPI are also important leads for the development of systemically active selective GABA(C) receptor antagonists.

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We report the synthesis of a series of 3-carboxy-, 3-(carboxymethyl)-, 3-(omega-phosphonoalkyl)-1-aminocyclobutane-1-carboxylic acids for evaluation as agonists or antagonists of neurotransmission at excitatory amino acid receptors, particularly N-methyl-D-aspartic acid (NMDA) receptors. The compounds were evaluated as agonists on their ability to depolarize the rat brain cortical wedge preparation or as antagonist of the actions of the selective agonists NMDA, quisqualic acid, and kainic acid. The chain-elongated glutamate derivatives with potential antagonist activity proved to be weak and frequently nonselective antagonists in this assay. The most noteworthy result was that trans isomer 7b was a very potent agonist, approximately 20 times more active than NMDA at NMDA receptors, while the cis isomer was 1/3 as potent as NMDA.