Mono N-aryl ethylenediamine and piperazine derivatives are GABAA receptor blockers: implications for psychiatry.

Ethylenediamine (EDA) and piperazine are known GABA-A receptor agonists and this activity appears to reside in their carbamate adducts. In CO2-free incubation medium EDA and piperazine weakly reverse the inhibitory action of 1 microM GABA on specific [35S]t-butylbicyclophosphorothionate (35S-TBPS) binding to rat brain membranes in vitro. In 25 mM sodium bicarbonate buffer, EDA and piperazine much more potently inhibit 35S-TBPS binding in a way reversible by the GABA-A receptor blocker R5135. Thus, native EDA and piperazine are weak GABA-A receptor blockers, while their presumed carbamate adducts, formed by reaction with bicarbonate, are more potent GABA-A receptor agonists. Virtually all structural modifications of EDA or piperazine result in GABA-A receptor blockers, even in the presence of bicarbonate, judging from their abilities to fully or partially reverse the inhibitory effect of GABA on 35S-TBPS binding. Of 12 non-aromatic piperazine or EDA derivatives, the piperazine derivatives are the more potent GABA antagonists, although all are weak compared to the mono N-aryl derivatives. Nineteen mono N-aryl EDA derivatives are moderately potent GABA antagonists, including 10 with demonstrated or potential antidepressant activity. Most of the N-aryl piperazines are moderately to highly potent GABA antagonists, one (pitrazepin) being 4 to 5 times more potent than bicuculline. There are several clinically effective antidepressants (e.g. Amoxapine, Mianserine) and antipsychotics (Clothiapine, Loxapine, Metiapine, Clozapine and Fluperlapine) among the more potent N-aryl piperazine GABA antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)