The neurotransmitter serotonin (5-HT) has been implicated in various physiological functions (e.g. memory, appetite, thermoregulation, sleep, nociception, sexual behavior) and in certain pathological/psychopathological conditions (e.g. depression, anxiety, Alzheimers disease, hallucinogenic behavior). With the relatively recent discovery of multiply populations of central 5-HT binding/receptor sites (e.g. 5-HT1A, 5-HT1B, 5- HT1C, 5-HT1D, 5-HT2) comes the possibility to ascribe a specific 5-HT-related effect to a particular type of 5-HT receptor. Unfortunately, rather little is known concerning the pharmacological and functional relevance of these receptors because of the lack of site-selective agonists and antagonists. The primary purpose of this proposal is (a) to develop high- affinity, site-selective 5-HT agonists and antagonists, (b) to evaluate these agents in pharmacological procedures that have proven useful, and (c) to develop an understanding of the molecular assemblies responsible for serotonergic affinity and selectivity. Specifically, we initially propose to synthesize certain aminotetralin analogs (5-HT1A antagonists), aryloxyalkylamines (5-HT1A antagonists), 4-alkylphenalkylamines (5-HT1C agonists and antagonists), aryloxyaminoalkyl amides (5-HT1A agonists and antagonists), and 4-alkyl 2,5-dimethoxyphenalkylamines (5-HT2 antagonists). Radioligand binding will be utilized to determine the affinity and selectivity of these agents for 5-HT (and other neurotransmitter) sites and the drug discrimination paradigm with rats as subjects, as well as other pharmacological studies, will be employed to document agonist vs antagonist activity. Over the last several years, an extensive series of preliminary studies was conducted in our laboratories; we now wish to exploit leads that we have developed. The long range goals of our work include the development of site- selective agents that will be useful for the evaluation of the functional significance of 5-HT receptors. Once agents with optimal affinity/selectivity have been obtained, they may be labeled for use in radioligand binding and autoradiographic studies. Such agents can also be utilized as new training drugs in future drug discrimination studies. Certain sites have not been thoroughly characterized (e.g. 5-HT1D, 5-HT3) or have not yet been identified in human brain (5-HT1B, 5-HT3); studies similar to those described above can ultimately be used to identify/study agents selective for these sites.
