MONO N-ARYL ETHYLENEDIAMINE AND PIPERAZINE DERIVATIVES ARE GABA(A) RECEPTOR BLOCKERS - IMPLICATIONS FOR PSYCHIATRY

Ethylenediamine (EDA) and piperazine are known GABA-A receptor agonist s and this activity appears to reside in their carbamate adducts. In C O2-free incubation medium EDA and piperazine weakly reverse the inhibi tory action of 1 muM GABA on specific [S-35]t-butylbicyclophosphorothi onate (S-35-TBPS) binding to rat brain membranes in vitro. In 25 mM so dium bicarbonate buffer, EDA and piperazine much more potently inhibit S-35-TBPS binding in a way reversible by the GABA-A receptor blocker R5135. Thus, native EDA and piperazine are weak GABA-A receptor blocke rs, while their presumed carbamate adducts, formed by reaction with bi carbonate, are more potent GABA-A receptor agonists. Virtually all str uctural modifications of EDA or piperazine result in GABA-A receptor b lockers, even in the presence of bicarbonate, judging from their abili ties to fully or partially reverse the inhibitory effect of GABA on S- 35-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, includin g 10 with demonstrated or potential antidepressant activity. Most of t he N-aryl piperazines are moderately to highly potent GABA antagonists , one (pitrazepin) being 4 to 5 times more potent than bicuculline. Th ere are several clinically effective antidepressants (e.g. Amoxapine, Mianserine) and antipsychotics (Clothiapine, Loxapine, Metiapine, Cloz apine and Fluperlapine) among the more potent N-aryl piperazine GABA a ntagonists. We suggest that the antidepressant and antipsychotic effec ts, as well as the convulsions, anxiety, panic attacks and insomnia ca used by the much studied 1-(m-chlorophenyl-piperazine) may be due to G ABA-A receptor blockade. It might be worthwhile to clinically test add itional N-aryl piperazines and N-aryl EDAs for antidepressant/antipsyc hotic activity.