The Synthesis and Activity of cis-and trans-2-(Aminomethyl) cyclopropanecarboxylic Acid as Conformationally Restricted Analogues of GABA

Abstract: The synthesis of cis -2-(aminomethyl) cyclopropanecarboxylic acid, a new analogue of GABA in a folded conformation, is described, as is also an improved preparation of trans -2-(aminomethyl) cyclopropanecarboxylic acid. When adminstered microelectrophoretically the trans isomer was more potent than GABA as a bicuculline-sensitive depressant of the firing of cat spinal neurons in vivo , whereas the cis-isomer was less potent than GABA and its effects appeared not to be sensitive to bicuculline methochloride. Trans -2-(aminomethyl) cyclopropanecarboxylic acid was a weak inhibitor of the sodium-dependent uptake of GABA by mini slices of rat cerebral cortex and a substrate for the GABA: 2-oxoglutarate aminotransferase activity in extracts of rat brain mitochondria. The cis isomer did not influence GABA uptake or aminotransferase activity and neither isomer reduced glutamate decar-boxylase activity in rat brain homogenates. Both cyclopropane isomers inhibited the sodium-independent binding of GABA to synaptic membranes from rat brain and their relative potencies together with those found for the stereochemically related unsaturated derivatives, cis -and trans -4-aminocrotonic acid, were broadly consistent with the activity observed for these compounds in vivo on cat spinal neurons. These studies reinforce the evidence that extended rather than folded conformations of GABA are active at most GABA recognition sites within the mammalian central nervous system.