Derivatives of uh 301 as Probes of the 5ht1a Receptor

Phase I describes a collaborative program that will synthesize a series of compounds related to(S)-5-F-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301], an antagonist of the serotonin 5HT1A receptor.Recently RBI has developed a procedure for the efficient synthesis of (S)-UH-301 that makes it feasibleto envision the synthesis of analogs and derivatives described in this proposal. In particular, there willbe 3 major activities during the initial 6 month feasibility study. First, [3H]-UH-301 will be synthesizedand tested for its ability to label the 5HT1A receptor expressed at high level in HeLa cells. Second, wepropose to develop a photoaffinity ligand based on the N-p-azido-phenethyl analog of (S)-UH-301 anddetermine if the molecule can photolabel the 5HT1A receptor stably expressed at high level in HeLa cells.We will then establish if the compound can be used to photolabel 5HT1A receptors in the brain. Third,we will synthesize a biotinylated analog of the p-amino-phenethyl analog of (S)-UH-301 and determineif it can be used to affinity purify 5HT1A receptors expressed at high level in cells. In Phase II, weanticipate fully characterizing the activity of the active molecules synthesized in Phase I. We willcharacterize the specificity of [3H]-UH-301, the photoaffinity probe and the affinity probe by testing themin binding assays for other 5HT receptors (as well as receptors for other biogenic amines). We willattempt to increase the specific activity of the radiolabeled derivative of (S)-UH-301 by incorporation of[125-I] into a congener. If desirable, we will synthesize additional derivatives in an attempt to enhancethe specificity and affinity towards the 5HT1A receptor.