(+) and (−)-bicuculline methochloride as optical isomers of a GABA antagonist

Abstract

THE discovery by Curtis et al.¹ that bicuculline would antagonise both the depressant effects of microiontophoretically applied γ-aminobutyric acid (GABA) and certain strychnine resistant central inhibitions has provided further support for the view that GABA might be a central transmitter. Their studies have also stimulated much thinking and research into the structural relationship of GABA and its receptor. On the basis of examination of Dreiding stereomodels of GABA and bicuculline, the Canberra group suggested that the nitrogen atoms and the three atoms associated with the carboxylate in GABA (O = C – O) could be isosteric with the nitrogen atom and the O = C – C grouping in bicuculline¹. Indeed, recent physiochemical work² on the two substances indicates that the distance from the onium group to a carboxylate oxygen in GABA is fixed at between 5.2 and 5.8 Å and this agrees well with a distance of 5.6 Å between the equivalent groups in bicuculline. It would therefore seem reasonable to suppose that the GABA antagonist properties of bicuculline are due to the occupation of the GABA receptor by a part of the bicuculline molecule that is isosteric with the biologically active conformation of GABA¹.