The objective of the proposed 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) in order to determine the structural features of compounds that determine optimal potency and selectivity at specific receptor subtypes. The ultimate goal of this work is the development of more potent and selective serotonergic agonists and antagonists to use as tools for the study of the functional roles of 5-HT in the CNS. The work is divided into two integrated parts: 1) the design and synthesis of new compounds and 2) the determination of the quantitative structure activity relationship of these compounds. Several different classes of compounds have been chosen for synthesis, based on previous studies. These include tetrahydropyridylindole analogs of RU 28253 and RU 24969, analogs of 8-hydroxy-2-(di-n-propylamino) tetralin, and certain aryltryptamines. Molecular modeling techniques will be used to determine the conformations and chemico-physical properties of the different compounds. Structure activity studies will utilize a combination of radioligand-binding assays and functional measures of receptor activation. Examples of 5-HT receptor subtypes to be studied using he ligand-binding technique include: 5-HT1A, 5-HT1D, 5-HT1C, and 5- HT2. Functional measures of 5-HT receptor subtypes will include the 5-HT1A receptor linked to the inhibition of adenylate cyclase, the 5-HT4 receptor, the vascular 5-HT2 receptor, a novel 5-HT2-like vascular receptor, and 5- HT1-like receptors in the cerebral vasculature. 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. 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. Information from such studies may ultimately 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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological Sciences Subcommittee 1 (NLS)
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University of Arizona
Schools of Pharmacy
United States
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Mellin, C; Vallgarda, J; Nelson, D L et al. (1991) A 3-D model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogues of 8-hydroxy-2-(dipropylamino)tetralin. J Med Chem 34:497-510
Cornfield, L J; Lambert, G; Arvidsson, L E et al. (1991) Intrinsic activity of enantiomers of 8-hydroxy-2-(di-n-propylamino)tetralin and its analogs at 5-hydroxytryptamine1A receptors that are negatively coupled to adenylate cyclase. Mol Pharmacol 39:780-7
Killam, A L; Nikam, S S; Lambert, G M et al. (1990) Comparison of two different arterial tissues suggests possible 5-hydroxytryptamine2 receptor heterogeneity. J Pharmacol Exp Ther 252:1083-9
Xiong, W C; Nelson, D L (1989) Characterization of a [3H]-5-hydroxytryptamine binding site in rabbit caudate nucleus that differs from the 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D subtypes. Life Sci 45:1433-42
Bates, R B; Bruck, M A; Camou, F A et al. (1989) 3-(1-Methyl-1,2,3,6-tetrahydropyrid-4-yl)indole. Acta Crystallogr C 45 ( Pt 1):109-11
Bjork, L; Hook, B B; Nelson, D L et al. (1989) Resolved N,N-dialkylated 2-amino-8-hydroxytetralins: stereoselective interactions with 5-HT1A receptors in the brain. J Med Chem 32:779-83
Cornfield, L J; Nelson, D L; Taylor, E W et al. (1989) MDL 73005EF: partial agonist at the 5-HT1A receptor negatively linked to adenylate cyclase. Eur J Pharmacol 173:189-92
Cornfield, L J; Nelson, D L; Monroe, P J et al. (1988) Use of forskolin stimulated adenylate cyclase in rat hippocampus as a screen for compounds that act through 5-HT1A receptors. Proc West Pharmacol Soc 31:265-7
Killam, A L; Nelson, D L; Nikam, S S et al. (1988) A comparison of putative 5-HT2 receptors in two different arterial tissues. Proc West Pharmacol Soc 31:95-7
Nikam, S S; Martin, A R; Nelson, D L (1988) Serotonergic properties of spiroxatrine enantiomers. J Med Chem 31:1965-8

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