5-Hydroxytryptamine Ligands

Although 5-hydroxytryptamine (1; 5-HT, serotonin) was detected in the mammalian CNS more than 40 years ago,(1) advances in the understanding of central serotonergic mechanisms lapsed behind those of other neurotransmitters, due chiefly to the relative lack of compounds with selectivity for 5-HT receptors. Hence stereochemical study of chiral 5-HT ligands has been limited, with the notable exception of investigations of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) described later. Interest in 5-HT receptors and their ligands has risen dramatically during the past decade and several valuable reviews on the topic are available.(2–7) The detection and subtype classification of 5-HT receptors rests heavily on the results of binding experiments, briefly outlined here. From work with [3H]5-HT, Peroutka and Snyder(8) proposed the existence of two major populations of central 5-HT binding sites, namely, 5-H1 sites labeled with high affinity by the natural ligand and 5-HT2 sites labeled (front cortex especially) by [3H]spiperidone. The ability of the DA-receptor ligand spiperidone to label 5-HT sites was originally reported by Leysen et al. (9) The further classification of 5-HT1 receptors followed observation that a portion of the binding of [3H]5-HT to brain receptor membranes was displaceable by low concentrations of spiperidone—such sites were subsequently termed 5-HT1A while sites insensitive to spiperidone were termed 5-HT1B.