GABA-Mimetic Activity and Effects on Diazepam Binding of Aminosulphonic Acids Structurally Related to Piperidine-4-Sulphonic Acid

ABSTRACT

The relationship between structure, in vivo activity, and in vitro activity of some analogues of the γ-aminobutyric acid (GABA) agonist piperidine-4-sulphonic acid (P4S) was studied. The syntheses of 1,2,3,6-tetrahydropyridine-4-sulphonic acid (DH-P4S) and (RS)-pyrrolidin-3-yl-methanesulphonamide (PMSA-amide) are described. Like P4S, its unsaturated analogue DH-P4S and the five-ring isomer (RS)-pyrrolidin-3-yl-methanesulphonic acid (PMSA) were bicuculline methochloride (BMC)-sensitive inhibitors of the firing of neurones in the cat spinal cord. Whereas isonipecotic acid was less potent than its unsaturated analogue isoguvacine as a GABA-mimetic and as an inhibitor of GABA binding, the opposite relative potencies of P4S and DH-P4S were observed, P4S being proportionally more potent than DH-P4S. In contrast with P4S and DH-P4S, PMSA, which is an analogue of the potent GABA uptake inhibitor and BMC-sensitive GABA-mimetic homo-β-proline, was a relatively weak inhibitor of GABA uptake in vitro. PMSA-amide was more than two orders of magnitude weaker than PMSA as an inhibitor of GABA binding and did not significantly affect GABA uptake in vitro. The effects of 3-aminopropanesulphonic acid (3-APS), PMSA, P4S, and DH-P4S on the binding of [³H]diazepam in vitro at 30°C, in the presence or absence of chloride ions, were studied and compared with those of the structurally related amino acids GABA, homo-β-proline, isonipecotic acid, and isoguvacine. Under these conditions the aminosulphonic acids were weaker than the respective amino acids in enhancing [³H]diazepam binding, the difference being more pronounced in the absence of chloride.