1488
J . Med. Chem. 1993,36, 1488-1495
Bridged y-Carbolines and Derivatives Possessing Selective and Combined Affinity for 5-HT2 and D2 Receptors Richard E. Mewshaw,*$tLisa S. Silverman,? Rose M. Mathew,? Carl Kaiser,? Ronald G. Sherrill: Menyan Cheng: Carol W. Tiffany,$ E. William Karbon,$ Michael A. Bailey: Susan A. Borosky,' John W. Ferkany: and Mary E. Abreut Scios Nova Inc., 6200 Freeport Centre, Baltimore, Maryland 21224-6522 Received January 28, 1993
A series of 5,6,7,8,9,10-hexahpdro-7,lO-iminocyclohept~blindoles and 6,7,8,9,10,11-hexahydro-7,ll-imino-5H-cyclooct[blindoleswas prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyll-5,6,7,8,9,1O-hexahydro-7,l0-iminocyclohept[blindole (5, Ki = 0.82 nM vs L3H1ketanserin) enabled the identification of the functionality necessary for high affinity at serotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety, were essential for high affinity. Variations of the length of the side chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and Dz affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-ll-[4-(4-fluorobenzoyl)butyll-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[blindole(36) had an ED50 of
