The CNS serotonin system is an important neurotransmission network regulating various physiological function and behavior. One of the serotonin receptor subtypes, 5-HT(1A) receptors, plays an important function as the somatodendritic autoreceptor (presynaptic) on 5-HT neurons, and as a postsynaptic receptor for 5-HT in terminal field areas. Buspirone and gepirone, partial agonists that display high affinity to 5- HT(1A) receptors, are presently being used as anti-anxiety agents. The development of selective 5-HT(1A) receptor ligands facilitates the study and characterization of this receptor with important implications for mental health. In the past few years, this project has developed a number of new ligands for 5-HT(1A) receptors. A new iodinated and selective 5-HT(1A) receptor agonist: [125I]R(+)-trans-8-OH-PIPAT, with high binding affinity (Kd=0.1 nM) was successfully developed by this project. New antagonists, MPPI (Kd=0.3 nM) and MPPF (Kd=0.23 nM), which showed high binding affinity and selective antagonist properties were reported. These new ligands became available for this program project and have provided powerful tools that are used by several other subprojects. In addition, radioactive forms of the antagonist radioligands, MPPI and MPPF (I-125 and H-3 labeled agents, respectively) are now available commercially for the general neuroscience community. These compounds were not available prior to this program project and the success we have had in this project led to the development of these new ligands as new tools for serotonin receptor research. This project serves, in part, a core function to provide """"""""cold"""""""" and """"""""hot"""""""" compounds (i.e., agonists and antagonists), which are not commercially available. These agents will be available for studies proposed in all of the other projects. In return, Project 1 will benefit from the material and information provided by the biological investigations of other subprojects. In addition, new selective agonists, antagonists, irreversible and photoaffinity labeling ligands for in vitro and in vivo binding of 5-HT(1A) receptors will be prepared and characterized. These new ligands are based on the agonist 8-OH-PIPAT, and antagonists MPPI and MPPF, which were developed in the previous funding period. When available, they will be supplied for use by several of the other projects in the program. They will provide powerful tools for elucidating the basic pharmacology of 5-HT(1A) receptors and their interactions with various agents currently being used for the treatment of mental illness, such as anxiety and depression.
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