Document Report Card

ID: ALA1127045

Journal: J Med Chem

Title: Bridged gamma-carbolines and derivatives possessing selective and combined affinity for 5-HT2 and D2 receptors.

Authors: Mewshaw RE, Silverman LS, Mathew RM, Kaiser C, Sherrill RG, Cheng M, Tiffany CW, Karbon EW, Bailey MA, Borosky SA.

Abstract: A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and 6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indoles was prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (5, Ki = 0.82 nM vs [3H]ketanserin) 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 D2 affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-11-[4-(4-fluorobenzoyl)butyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (36) had an ED50 of < 1 mg/kg at the 5-HT2 and D2 receptors following oral administration.

CiteXplore: 8496917

DOI: 10.1021/jm00062a023