# Structural Studies and Drug Discovery Illuminate Serotonin Pharmacology

> **NIH NIH R35** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $447,850

## Abstract

Project Summary/Abstract
The main goal of the lab is to provide detailed structural and functional insight into serotonin signaling and
transport, and elucidate how drugs and medications modulate receptor and transporter function. Serotonin (5-
hydroxytryptamine, 5-HT) regulates much of human physiology in- and outside the CNS, including cognition,
mood, endocrine function and cardiovascular development. However, despite 5-HT's physiological and medical
importance, atomic-level insight into the mechanisms of 5-HT signaling and transport, and how drugs interact
with these molecular targets has remained incomplete. This lack of understanding has led to drug safety issues
in the past, and greatly hindered the exploration of many 5-HT targets for novel therapeutic applications. Our
lab thus focuses on three major directions to address these gaps. Firstly, we aim to investigate the molecular
mechanisms by which 5-HT receptors signal through different transducers using structural and biochemical
approaches. For instance, we will delineate the molecular determinants of how the 5-HT1A receptor signals via
different G proteins of the Gi/o/z family, and elucidate how different drugs affect the receptor's conformational
landscape to engage distinct signal transducers. A second major direction is to structurally and functionally
characterize off-target activities of serotonergic drugs at understudied serotonin-related transporters such as
the vesicular monoamine transporter 2 (VMAT2) or organic cation transporters (OCTs). Through these studies,
we aim to provide a molecular level context of side effects reported for commonly prescribed drugs, but also to
uncover the fundamental mechanistic properties of these understudied transporters. This work will further
elucidate modulatory drug binding sites at these transporters and allow contrasting them with those found at 5-
HT receptors. Lastly, we also aim to harness our structural and functional insights to develop target-selective
and pathway-specific probes for both 5-HT receptors and transporters. The goal here is to generate chemically
and pharmacologically novel and useful tools that enable inquiries into serotonin-related (patho)biology in vitro
and in vivo. Our studies are both innovative technically and conceptually, as the unique combination of
structural, pharmacological, and drug discovery approaches as well as the focus on both receptors and
transporters will provide a holistic framework of serotonin-related biology and pharmacology at the molecular
scale.

## Key facts

- **NIH application ID:** 10842533
- **Project number:** 2R35GM133504-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Daniel Wacker
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $447,850
- **Award type:** 2
- **Project period:** 2019-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842533

## Citation

> US National Institutes of Health, RePORTER application 10842533, Structural Studies and Drug Discovery Illuminate Serotonin Pharmacology (2R35GM133504-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10842533. Licensed CC0.

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