The objective of the project is the pharmacologic characterization of the properties of the different types of serotonin (5-hydroxytryptamine, 5-HT) receptors in the mammalian central nervous system (CNS). Coupled with this is a program for the design and systhesis of new compounds in an effort to develop more potent and selective serotonergic agonists and antagonists to use as tools for the study of the functional roles of 5-HT-containing neurons. Extensive series of compounds in three major classes of structures will be examined. These include indoleamine analogs (tetrahydropyridylinodoles and arylsubstituted tryptamines), spiroxatrine analogs, and aminotetralin derivatives. A major part of the characterization of the receptors and screening of new compounds will involve the use of radioligand-binding techniques to measure the following subtypes of central 5-HT receptors: 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2. Another part of the project will be the characterization of functional 5-HT receptors both in vitro and in vivo. Of special interest is the cerebral vasculature, which unlike the peripheral vasculature appears to receive innervation from central serotonergic neurons and to contain 5-HT1A receptors. Additional functional studies will examine the actions of the compounds at 5-HT-modulated temperature regulation and in the serotonin syndrome. The study of functional 5-HT receptors will provide information as to whether the compounds are agonists, antagonists, or partial agonists and whether the properties of the functional receptors correlate with those of the putative receptors measured by ligand-binding. As with the ligand-binding studies, a major emphasis of this portion of the project will be the attempt to determine the structural requirements of compounds for discrimination between different types of 5-HT receptors. Once the properties of these groups of receptors are characterized, it is hoped that more selective drugs can be designed that will facilitate the study of the roles and actions of 5-HT in the CNS. It is hoped that information from such studies can be used for the design of new, more effective therapeutic agents for the treatment of physiologic and mental disorders that are thought to be linked to abnormal serotonergic function in the central nervous system.
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