Epimeric cis-decahydroquinoline-5-carboxylic acids: effects on .gamma.-aminobutyric acid uptake and receptor binding in vitro

Abstract

The syntheses for 2 cis-decahydroquinoline-5-carboxylic acid epimers which contain the.dbd.N(C)3CO2H GABA moiety are described. Both intra- and intermolecular [4 + 2] cycloaddition reactions were used for the construction of key intermediates. MR studies provided evidence for the preferred solution conformations of the 2 diastereomers. Pharmacological studies revealed that these isomers have little affinity for rat GABA receptors in vitro relative to GABA agonists. Expected but weak, stereoselective activity was observed when these analogs were assessed for their ability to inhibit high-affinity [3H]GABA uptake into rat brain synaptosomes. These data are discussed in light of structure-activity studies of other neurotransmitter analogs, and a preliminary hypothesis based upon conformational analysis is presented to explain the results.