The need to develop selective compounds for 5-HT receptors requires further elucidation of structure-activity relationships involved with receptor recognition and activation. In particular, there is great interest in the involvement of the 5-HT₁(A) receptor in therapeutic treatment of conditions such as anxiety, depression and hypertension. Despite previous attempts to define the pharmacophore for 5-HT₁(A) receptors, the structural requirements for 5-HT₁(A) receptor activity remain largely unexplored. In fact, no selective 5-HT₁(A) antagonists currently exist. Binding assays provide important information concerning receptor affinity, but do not reflect functional consequences of receptor interaction. One of the functional correlates of the 5-HT₁(A) receptor is the inhibition of forskolin-stimulated adenylate cyclase (FSC). The objective of this dissertation was to assess the merits of using the FSC assay as a functional screen to determine 5-HT₁(A) intrinsic activity of novel compounds. From the variety of compounds tested, it was apparent that the FSC assay can be used as an in vitro functional screen for assessing 5-HT₁(A) agonistic and antagonistic, as well as partial agonistic, activity. All putative 5-HT₁(A) agonists tested in the FSC assay had potencies (EC₅₀) that were less than their respective 5-HT₁(A) binding affinities (Kᵢ). The use of pindolol to block 5-HT₁(A) receptors, and therefore cause a rightward shift in any observed inhibition curve, provided qualitative evidence of 5-HT₁(A) interaction. Quantitative evaluation of 5-HT₁(A) activity had to be approached cautiously, due to possible complications arising from non-5-HT₁(A)-mediated inhibition. The data for a series of enanatiomers of 8-OH-DPAT and its analogs supported a recently proposed model for the 5-HT₁(A) agonist pharmacophore. Also, within the enantiomeric pairs exhibiting stereoselectivity, the compound with the higher 5-HT₁(A) affinity also possessed greater 5-HT₁(A) agonistic activity. Within a series of tetrahydropyridylindoles (THPI), the 4-THPI analogs generally had both greatest 5-HT₁(A) affinity and agonistic activity, although there were exceptions to this trend. Several compounds, whose structures were based on the small molecules of the 5-HT₁(A) agonist 8-hydroxy-2-(di-n-propylaminotetralin) (8-OH-DPAT) and 5-HT itself, demonstrated potential antagonistic activity in the FSC assay. Further analysis of an extended series of these compounds in the FSC assay is required to establish specific conclusions concerning the 5-HT₁(A) pharmacophore.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/185101 |
| Date | January 1990 |
| Creators | Cornfield, Linda Joan. |
| Contributors | Nelson, David L., Laird, II.,Hugh E., Liebler, Dan C., Regan, John W., Yamamura, Henry I. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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