Synthesis of 6-substituted beta-carbolines that behave as benzodiazepine receptor antagonists or inverse agonists.
The synthesis of the first beta-carboline, 6-(benzylamino)-beta-carboline (1c), to be devoid of a substituent at the 3-position and that still binds to benzodiazepine receptors with potent affinity is described. Furthermore, 1c proved to be a partial inverse agonist when tested in mice. Addition of the benzylamino group at the 6-position of the beta-carboline nucleus is primarily responsible for the activity of beta-carbolines 1b and 1c. The importance of the Nb-nitrogen atom for binding affinity was also demonstrated since 3-(benzylamino)carbazole (6) exhibited little or no affinity for benzodiazepine receptors in vitro, in contrast to the activity of 1c.
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000627:therapeutic use; D002243:Carbolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors / Q000633:toxicity; D011485:Protein Binding; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D002243:Carbolines; D011963:Receptors, GABA-A; D010433:Pentylenetetrazole