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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS016605-06
Application #
3397002
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1981-12-01
Project End
1989-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
6
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Pharmacy
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
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
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
Taylor, E W; Nikam, S S; Lambert, G et al. (1988) Molecular determinants for recognition of RU 24969 analogs at central 5-hydroxytryptamine recognition sites: use of a bilinear function and substituent volumes to describe steric fit. Mol Pharmacol 34:42-53

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