The objective of the proposed project is the characterization of the properties of the different types of serotonin (5-hydroxytryptamine, 5-HT) receptors in the mammalian central nervous system (CNS). One part of this involves the use of in vitro binding assays utilizing ligands such as 3H-5-HT and 3H-ketanserin, which are thought to label specific populations of serotonin receptors. A major emphasis of this work will be the pharmacological characterization of these receptors to determine the structural requirements of compounds for discrimination between different types of 5-HT receptors. In conjunction with the ligand-binding assays a program for the synthesis of new compounds will be carried out. Thus, information from the binding assays will be used for the design of new compounds for testing at 5-HT receptors. Another part of the project will be the characterization of functional 5-HT receptors, both in vitro and in vivo. This will include examination of 5-HT receptors which mediate contraction of the cerebral vasculature and the rat fundus and examination of central 5-HT receptors involved in the control of respiration, blood pressure, body temperature, and release of certain pituitary hormones such as prolactin and thyrotropin. The study of functional receptors will provide information as to whether the compounds are agonists or antagonists of 5-HT 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 these groups of receptors are classified and characterized, it is hoped that more specific drugs can be designed which 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 behavioral or 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 #
5R01NS016605-04
Application #
3397006
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1981-12-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
4
Fiscal Year
1985
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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