Perhaps the best year for conducting research on selective serotonergic agents was 1980; at that time, one need only be concerned with selectivity for 5-HT1 vs 5-HT2 receptors. This situation has changed dramatically with the discovery of at least 14 different 5-HT receptor subpopulations. As entirely novel lead structures are developed, there is increasing possibility that an agent might bind at a nonserotonergic receptor.
For the most part, the vast majority of agents showing any degree of selectivity that are used in serotonin research were (or were derived from) chance discoveries. This is certainly true of the older agents such as DOM (6), 8-OH DPAT (9), ketanserin (15), NAN-190 (37), and many others. Synthesis of structurally related analogs of these serendipitously identified ligands to achieve enhanced selectivity became the norm. However, even here, little design rationale was actually employed (or at least the rationale was not always revealed in literature reports). Available agents were often used to identify pharmacological assays that then could be used, in turn, to screen compounds on a compound-by-compound basis and, more recently, via high-throughput screening methods. Nevertheless, although a number of lead structures or structural templates were identified over the years, additional efforts were frequently required to obtain ligands with the desired selectivity. Medicinal chemists working in the serotonin field have risen to the challenge and numerous selective agents are now available for many (although not all) 5-HT receptor types. In most instances, the key was identification of a "lead structure" using either a structured research approach or serendipity. Perhaps the first example of the purposeful development of a selective serotonergic agent was that by Fozard and colleagues. Taking advantage of findings that cocaine and metaclopramide behaved as M-type serotonin receptor antagonists, they prepared hybrid structures that eventually represented the first 5-HT3-selective antagonists (reviewed in ref. 18). Two recent tales of ligand development are those leading to newer analogs of the 5-HT6 antagonists 66 and 67. Whereas 66 and 67 were originally identified via high-throughput screening, the pharmaceutical industry was able to take advantage of these new lead structures. Here, in addition to selectivity enhancement, Pharma needed to concurrently tackle optimization of bioavailability and other pharmacokinetic properties. These studies have been summarized and reviewed (6,104).
This chapter describes some of the methods we have employed in our laboratory to develop selective serotonergic agents—in particular, the deconstruction-reconstruction-elaboration approach and the standard series approach—as pharmacological tools. The former is something that some medicinal chemists do (perhaps subconsciously) when, for example, formulating pharmacophore models (i.e., in determining the minimal base structure associated with a given activity); we have simply formalized the approach somewhat to systematically develop novel ligands with greater selectivity than the agents from which they were derived. The standard series approach has been especially useful in identifying new leads for subsequent development in the serotonergic area because there are so many 5-HT receptors, all of which utilize serotonin as the natural ligand. Lacking other viable starting points, the structure of serotonin is frequently the only structural template available to initiate such studies. In the course of our work, we have also applied graphics modeling, QSAR methods, and other techniques; as already mentioned, however, these typically require input that might not be available before a lead structure has been identified. Our investigations were also aided by a good dose of serendipity. In short, several different methods have been applied to the development of agents with selectivity for various serotonin receptors. Continued application of these methods should allow the further development of ligands with even greater selectivity and, possibly, the identification of agents selective for serotonin receptors for which selective agents do not currently exist.
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