Synthesis of 3,6-Disubstituted b-Carbolines Which Possess either Benzodiazepine Antagonist or Agonist Activity

Abstract

AAbSrracr -A series of 3~substituted and 3.6-disubstituted p-carbolincs have been synrhesiccd.These compounds have been screenedvifro in order t o determine the size of substituenrs which benrodiizepine receptors will tolerate at positions 3 and 6 o f the 0-carboline nucleus.If has been found that the receptor will tolerate e s t e r d k y l groups a t poaition~?as large as cyclohexyl but not as large as adimmryl Sd *loreover, N~aryl subsfiiuenfs as large as naphrhobenzylamino 8b c m be introduced a t position-6 without significant 105s of receptor binding affinity.N~~~~~~ p ~~a r b o l i n ~~3 ~~~~b ~~~l a f e s have been s h o w to be antagonisrs of the benzodiazepines.For example. the ethyl ester (BCCE) antagonized the anticonwlsanr effects of dia~eparn,"~ the anticonflict activity of lorazepam and d i a ~e p a r n , ~' ~ and the ataxic effects of diazepam as demonstrated in the horizontal wire similar benzodiazepine antagonist properties have been demonstrated for the propyl ester (PCC) and the rnerhyl carboxamide.~~-71&2.~"""BCCE also blocks the effects of benzodiazepines, measured e ~e c r r o p h y s i o l o g i c a l l y .~ a s well as blocking the decrease in levels of cerebral cyclic GMP caused by benzodiazepinesB The t-bury1ester (BCCt), in fact, has been shown ro reverse midazolam-ethanol induced GNS depression suggesrirg these effects may be mediated through the benzodiarepi,le receptory tiowever, 6~~~~b o l i n e s such as BCCE and the mechyl ester.BCCM, are not antagonists of the benzodiazepines.Rather, they appear to be inverse agoniste10 since they produce effects which are opposite to those of the benzodiazepines.In this regard BGCE has been shown to potenciare