# Instrument Supplemental Grant

> **NIH NIH R16** · FLORIDA AGRICULTURAL AND MECHANICAL UNIV · 2024 · $99,488

## Abstract

Contact PD/PI: Ablordeppey, Seth
Funded Project Summary/Abstract: Numerous studies have indicated that 5-HT7R plays a
significant role in various psychophysiological functions such as mood stability, cognitive and motor
functions, pain tolerance, sleep patterns, appetite, and thermoregulation. Pre-clinical findings have
established the role of 5-HT7R in autism spectrum disorders, Fragile X syndrome (FXS), epilepsy,
sleep disorders, neuropathic pain and migraine. Meanwhile, several 5-HT7R agonists, have been
reported and their potential use in various CNS conditions are being investigated. However, the
beneficial effects of activation or blockade of the 5-HT7R is not often clearly established, primarily due
to the lack of selective 5-HT7R agents. Even more critical is the absence of biased ligands that could
clarify several controversial observations that relate to the 5-HT7R. Thus, our goal to design,
synthesize and pharmacologically evaluate new agents with biased signaling towards G-Protein or β-
arrestin signaling pathways hold great promise in understanding the 5-HT7R and its application to the
treatment of various CNS disorders. Three specific aims (SAs) are proposed. SA 1 will focus on
extending our studies on the lead agents for their drug-like properties including brain penetration,
pharmacokinetic, metabolic, and bioavailability assessments and cardiotoxicity predictions (HERG, 5-
HT2BR). Based on the metabolic evaluations of lead compound 55933, the synthesis and screening of
new compounds is proposed in SA 2. This specific aim will also focus on optimization and design of
new agents to address the metabolic stability issues such as aromatization and glucuronidation
observed in the preliminary studies. For this reason, aromatization susceptible tetrahydroisoquinoline
moiety will be replaced with isoindoline which could not undergo aromatization and the CH2OH
group will be replaced with substituents such as -F, -CONH2 to restrict glucuronidation. In addition,
exploring the electron donating/ withdrawing (σ values) and hydrophilic/hydrophobic (pi values)
space around the THI/isoindoline ring systems with bioisosteric substituents, will reveal any
improvements in their drug-like characteristics. Simultaneously, docking studies will be carried out
using homology models to identify interactions with the key amino acid residues involved in inducing
conformations associated with β-arrestin recruitment to the 5-HT7R. SA 3 will cover functional
selectivity studies of lead 5-HT7R ligands for their agonist/antagonist properties and G-Protein or β-
arrestin signaling bias followed by evaluation of their effect on sleep architecture and NREM/REM
sleep pattern under in vivo conditions. Finally, selected test compounds will be compared with
SB269970 (5-HT7R antagonist) and compound 1g, a 5-HT7R partial agonist (as a positive control) for
their effect on NREM/REM sleep pattern in a mouse model.
Progress Report Summary of Parent Award: The full progress...

## Key facts

- **NIH application ID:** 11035828
- **Project number:** 3R16GM145581-03S1
- **Recipient organization:** FLORIDA AGRICULTURAL AND MECHANICAL UNIV
- **Principal Investigator:** Seth Y Ablordeppey
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $99,488
- **Award type:** 3
- **Project period:** 2022-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11035828

## Citation

> US National Institutes of Health, RePORTER application 11035828, Instrument Supplemental Grant (3R16GM145581-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11035828. Licensed CC0.

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