# Research Project-2: Functionally Selective Ligands Targeting 5-HT7 Receptor as Potential Antinociceptive Agents

> **NIH NIH U54** · FLORIDA AGRICULTURAL AND MECHANICAL UNIV · 2024 · $250,142

## Abstract

Project Summary/Abstract: Neuropathic pain is estimated in the general population to range between 3%
and 17%, and lacks an effective treatment, as most of the available treatments have only moderate efficacy
and present significant side effects including addiction that limit their use. Therefore, other therapeutic
approaches are needed to replace the addictive opioids that are the mainstay of current treatment.
5-HT7R agonists including AS-19, E-55888, LP-12, LP-44, LP-211, AGH-192 and compound 1g have been
reported in the literature and have been used to characterize the involvement of the 5-HT7R in CNS conditions
including pain, memory and cognition. More recently, 5-HT7R agonists have been implicated in the treatment
of neuropathic pain, sleep disorders, and alcohol and drug abuse. However, there are divergent views reported
in the literature regarding the role of the 5-HT7R ligands in their pharmacological actions. While these
controversial roles of 5-HT7R may depend on non-selectivity at other CNS receptors, and/or on different brain
regions and the neurochemical environment in which the receptors are located, or even receptor-receptor
interactions, some of the inconsistent pharmacological effects may be explained by the different signaling
pathways associated with the 5-HT7R, including G protein biased, β-arrestin biased or balanced signaling at
both pathways. Current evidence indicates that 5-HT7R ligands activate not only G protein but also β-arrestin
signaling pathways and that no β-arrestin-biased ligands that selectively interact with 5-HT7R have been
disclosed other than compound 1g reported in a JMC paper in 2018. In addition, a recent PNAS paper reported
serodolin behaves as an antagonist/inverse agonist on Gs signaling while inducing ERK activation through a
β-arrestin–dependent signaling mechanism that requires activation of the non-receptor tyrosine kinase, c-Src.
Serodolin was also shown to decrease hyperalgesia and pain sensation in response to inflammatory, thermal,
and mechanical stimulation. Thus, in this proposal, we hypothesize that 5-HT7R ligands that recruit β-arrestin
to the receptor would produce antinociceptive effects and may serve as alternatives to the use of opioids.
To begin addressing several of these issues, we have proposed three specific aims as follows: Specific Aim 1
will optimize the very high affinity (5-HT7R, Ki = 0.16 nM) lead compound (55933) by designing, synthesizing,
and evaluating the binding affinities of new agents that are more drug-like and capable of improving 55933’s
metabolic profile. Specific aim 2, will investigate the drug-like characteristics of optimized lead compounds
identified and/or proposed in specific aim 1 including their brain permeability. And in specific aim 3, the in vivo
efficacy evaluation of test compounds for antinociception and neuropathic pain will be carried out.

## Key facts

- **NIH application ID:** 11001307
- **Project number:** 2U54MD007582-39
- **Recipient organization:** FLORIDA AGRICULTURAL AND MECHANICAL UNIV
- **Principal Investigator:** Seth Y Ablordeppey
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $250,142
- **Award type:** 2
- **Project period:** 1997-08-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11001307

## Citation

> US National Institutes of Health, RePORTER application 11001307, Research Project-2: Functionally Selective Ligands Targeting 5-HT7 Receptor as Potential Antinociceptive Agents (2U54MD007582-39). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11001307. Licensed CC0.

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