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

The syntheses for two cis-decahydroquinoline-5-carboxylic acid epimers (1 and 2) which contain the =N(C)3CO2H (gamma-aminobutyric acid; GABA) moiety are described. Both intra-and intermolecular [4 + 2] cycloaddition reactions were employed for the construction of key intermediates. 1H NMR studies provided evidence for the preferred solution conformations of the two diastereomers. Pharmacological studies revealed that these isomers have little affinity for GABA receptors in vitro relative to GABA agonists. However, expected but weak stereoselective activity was observed when these analogues 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 analogues, and a preliminary hypothesis based upon conformational analysis is presented to explain the results.