6-Substituted tricyclic partial ergoline compounds are selective and potent 5-hydroxytryptamine 1A receptor agents

Abstract

A series of 6 tricyclic partial ergoline derivatives was analyzed using radioligand binding assays. Four agents (LY 178210, LY 254089, LY 197205, and LY 197206) display high affinity (K i 1.3 nM) for 5-hydroxytryptamine 1A (5-HT 1A) receptor binding sites labeled by [ 3H] 8-hydroxy-2-(d1-n-propylamino) t tetralin (8-OH-DPAT) and display ⩾ 150 fold selectivity for the 5-HT 1A over the 5-HT 1D receptor binding site. The most potent agent investigated, LY 178210, is essentially inactive (K i > 1500 nM) at a total of 12 other neurotransmitter receptor binding sites in the brain. Using a forskolin-stimulated adenylate cyclase assay as a model of 5-HT 1A receptor function, LY 178210 was found to display partial agonist activity which was blocked by 10 −5 M (-) pindolol. These data indicate that LY 178210 is a potent and selective 5-HT 1A receptor partial agonist.