NOVEL SEROTONIN UPTAKE INHIBITOR LIGANDS

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The serotonin (5-HT) transporter complex is a protein located on the pre-synaptic side of serotonergic neurons in the central nervous system and is involved in regulating concentrations of 5-HT (uptake) in the synaptic cleft. This protein contains a binding site for serotonin and is thought to play a critical role in a variety of mental health disorders. The 5-HT binding site can be blocked. This site has been-shown to be the target of many of the commercial, highly selective antidepressants and also of drugs of abuse, including cocaine. Our long-term objective is to further elucidate the structure of the 5-HT uptake inhibitor binding site. The study will develop new chemical probes and perform computational modeling studies in order to refine a prelminary three-dimensional model of the inhibitorypharmacophore and employ computer-aided three- dimensional quantitative structure-affinity relationship (3D-QSAR) comparative molecular field analyses to map the 5-HT uptake binding site. To accomplish these goals, our specific aims encompass I)the syntheses and in vitro binding evaluations of semi-rigid and flexible quinolyl- and indolylphenylalkylamine molecules; 2) the syntheses and assessments of in vitro binding at the 5-HT uptake receptor of phenylazepinoindole ligands and also dinor-12- hydyroxyibogaine; and 3) computer-aided modeling employing an active analog approach effected by template forcing, conformational analyses for construction and refinement of the ligand based pharmacophore 5-HT uptake model followed by the utilization of a refined pharmacophore model for the application of a 3D-QSAR comparative molecular field analysis. The resultant binding site map may prove to be potentially useful for its binding affinity prediction value which will be used for the design of other structurally novel drugs with enhanced biochemical properties and high binding affinities for the serotonin uptake site. New drugs afforded from this design paradigm may find application as new therapies or as diagnostic tools in serotonin related mental health disorders.