Higher-end serotonin receptors:: 5-HT5, 5-HT6, and 5-HT7

5-HT5, 5-HT6, and 5-HT7 receptors were first discovered (i.e., cloned and expressed) within the past 10 years. Most of the 1990s was devoted to characterizing these receptors (or subtypes or splice variants). It was only in the very late 1990s that clues began to emerge regarding the development of selective agents, and this work for the most part continues today. It is perhaps appropriate that a Perspective article on these receptor populations follows a most recent Perspective article on 5-HT4 receptors and their ligands. As 2003 begins, no 5-HT5-selective agonists or antagonists have been identified. Progress has been slow on 5-HT5A receptors, and that on 5-HT5B receptors is virtually nonexistent. In fact, there is still some controversy regarding the 5-HT5 second messenger, and a function for 5-HT5 receptors has yet to be clearly demonstrated. 5-HT6 receptors, of the three receptor types discussed in this article, have seen the most progress. A sufficient number of useful and selective antagonists (and radioligands) have been identified, and the function of these receptors is now a matter of serious investigation. The one agonist showing some selectivity for 5-HT6 receptors has seen little investigation. A novel 5-HT6 agonist with a conformationally constrained side chain, 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (IC50 = 6 nM) was recently reported in an abstract by Merck. 5-HT7 receptors are beginning to emerge from the shadows, and identification of a putative 5-HT7 pharmacophore model might aid further progress in this area. 5-HT7 receptor splice variants and their constitutive activity require further investigation. Nevertheless, some interesting antagonists have been reported and time has arrived for greater application of these agents in functional studies. To date, no 5-HT7-selective agonist has been reported. In general, as described above, some progress has been made toward the development of selective agents for these three receptor populations, and where such agents are unavailable, certain lead structures have been identified. Site-directed mutagenesis and construction and evaluation of chimeric 5-HT receptors could provide additional leads for synthesis of selective agents. The three receptor types discussed herein have been implicated in a broad variety of physiological processes and possible disease states, both central and peripheral. Because most of these have been implications based on receptor localization studies or perhaps the results of individual empirical studies or studies using nonselective agents with different binding profiles and pharmacologies, greater effort is required to substantiate the claims and proposed therapeutic applications. With the recent emergence of novel chemical tools and with continued development of required selective agonist and/or antagonist ligands, answers should be forthcoming in the relatively near future.