STRUCTURE-ACTIVITY-RELATIONSHIPS IN ANTAGONIST AND INVERSE AGONIST LIGANDS FOR THE BENZODIAZEPINE RECEPTOR

The X-ray crystal and molecular structures of the three benzodiazepine (BZD) receptor ligands are presented and the electronic character of inverse agonist ligands is probed through molecular orbital calculatio ns. Two of the ligands have a 6-benzylamino substituent: 6-benzylamino -beta-carboline-3-carboxylic acid methyl ester, 1, which is a high aff inity antagonist with IC50 = 10 nM, and 6-benzylamino-beta-carboline, 2, which is a moderate affinity inverse agonist with IC50 = 106 nM. Th e third compound, 3-ethoxy-beta-carboline hydrochloride, 3, displays p artial inverse agonist activity with an IC50 Of 24 nM. Intermolecular interactions, including extensive hydrogen bonding involving both the pyridyl nitrogen atom and the indole N-H as well as pi stacking of aro matic rings, are characteristic of beta-carbolines and are found in th ese three structures. In addition, two of these compounds are protonat ed in the crystalline state, thereby providing a model for interaction s in the absence of the 3-carboxylic acid ester function. Electronic c alculations show that (1) the partial inverse agonist ligand has the h ighest charge on the N(2) atom and (2) high affinity beta-carbolines p ossess two neighboring sites that have high electrostatic attraction f or a hydrogen atom in an intermolecular interaction. These findings su ggest that modifications to the 3-position side chain to enhance the c harge on the pyridyl N atom and provide a hydrogen bond acceptor site will facilitate the development of partial inverse agonist ligands.