Structure-activity relationships at 5-HT1A receptors: binding profiles and intrinsic activity

The 5-HT1A receptor has been one of the most studied 5-HT receptor subtypes in terms of its pharmacologic profile. Comparisons of various studies of structure-activity relationships (SAR) at this receptor shows an emerging profile for this receptor's pharmacophore. The present discussion focuses on the findings generated with relatively small molecules that can be considered as analogs of serotonin itself and that illustrate some of the structural properties that are important for high-affinity recognition by the receptor. Most of the SAR work has been based on the affinities of compounds for the receptor as determined by the radioligand-binding technique, which has a significant limitation in that it cannot define the intrinsic activity of compounds at the receptor. This problem can be addressed by functional assays, and an example of SAR at the 5-HT1A receptor-coupled adenylate cyclase system is provided.