Structure-activity studies of β-carboline analogs

A number of β-carboline analogs have been obtained or synthesized, and their $\text{in vitro}$ receptor affinities and $\text{in vivo}$ antagonist activities determined. The choice of analogs was made in order to explore the importance of the N₉-H, the aromatic nitrogen and the C₃-ester moiety for high-receptor affinity and antagonist activity of this class of benzodiazepine antagonist. Among the analogs investigated, we describe the properties of 3-cyano-β-carboline ($\text{lh}$), the first potent β-carboline antagonist without a carbonyl at the C₃-position.The results obtained indicate: (1) Specific interactions of the C₃-substituent with key cationic receptor sites rather than electron-withdrawing properties are important for high-receptor affinity and antagonist activity. (2) Specific in-plane interactions of the atomatic nitrogen with a cationic receptor site, rather than stacking with neutral aromatic residues of the receptor are also important for high affinity and antagonist activity. (3) While the presence of an N₉H enhances receptor affinity, interaction with an anionic receptor site does not appear essential for antagonist activity.