Using Other Compounds

Thus, using an iterative process, we started to put bits and pieces together by comparing the binding profiles of radioligands known to interact with 5-HT/Dopamine D1-D2/5-HT2 or mixed 5-HT2/D2, beta-receptor ligands, and the one that seems to label pretty much everything, [3H]LSD and its derivative [125I]LSD. In fact, [125I] SCH23982 and [125I]LSD were characterized in the choroid plexus and found to label 5-HT1C sites (Hoyer et al. 1986b). We also used [3H]OH-DPAT, which at the time was (and still is) an exquisite tool to define 5-HT1A sites, whereas [3H]ketan-serin turned out to be another valuable tool for labeling 5-HT2 receptors. Both membrane and autoradiographic studies allowed us to define the pharmacological profile of affinities on the new receptor, with the drugs available at that time - in addition to 5-HT and mesulergine, LSD, methysergide, and mianserin were among the compounds showing high or very high affinity for 5-HT1C receptors; ketanser-ine, pirenperone, and methergine bound to the new site with an intermediate affinity; finally, 8-OH-DPAT (a 5-HT1A drug), the beta-blocker and 5-HT1B compound (-) 21009 and spiperone demonstrated low or very low affinity for the new recognition site (Hoyer et al. 1985a).

The iterations were multiple: Radioligand binding was performed in brain membranes, including choroid plexus, receptor autoradiography in brain slices of various species, and whichever other functional models could be used, e.g., contractions of the guinea-pig ileum (Engel et al. 1984; Kalkman et al. 1986), inhibition of 5-HT release in the cerebral cortex (Engel et al. 1986), stimulation or inhibition of cAMP

production in hippocampus (Markstein et al. 1986; Schoeffter and Hoyer 1989a) in the substantia nigra (Schoeffter and Hoyer 1989b), stimulation of PLC production in choroid plexus (Hoyer et al. 1989) or in smooth muscle cells, and contraction or relaxation of various vessels (Hoyer 1988a).

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