Synthesis and Structure-Activity Relationships of 1-Aryl-β-carbolines as Affinity Probes for the 5-Hydroxytryptamine Receptor

Abstract

Simple β-carbolines have been shown to bind several protein receptors that are important for signaling in the central nervous system. Herein, we expand our previous efforts into the synthesis and biological activity of these heterocycles by studying their neuropharmacological activity. A diverse set of 1-aryl-β-carbolines has been synthesized via Suzuki cross-coupling from a common triflate precursor and several substituted aryl boronic acids. The resulting 26-member library was subjected to primary screening at 10 μM for activity against 40 protein receptors implicated in brain signaling. The Ki was subsequently determined for several lead structures. The most potent activity, as low as 100 nM, was found against the 5-hydroxytryptamine subtype-2 family of receptors. In-depth structure-activity relationships for these synthetic β-carbolines have been developed, which point to the importance of a 3-indolyl substituent attached to the 1-position of the β-carboline and a 6-methoxy substituent on the β-carboline core.