# Endocannabinoid Active Sites as Therapeutic Targets

> **NIH NIH P01** · NORTHEASTERN UNIVERSITY · 2022 · $1,477,010

## Abstract

RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT SUMMARY/ABSTRACT
In this Program Project renewal application, we propose to fundamentally expand current understanding of the
variable potentially functional modulations of the CB1 and CB2 cannabinoid receptors.
During this current period, our work has resulted in the development of a number of key pharmacologically
diverse and selective agonists and antagonists for CB1 and CB2 cannabinoid receptors. We also produced
detailed information on the structures of these two receptors. Based upon the strengths of this foundational work,
we now propose to develop new functionally selective tools for fine tuning CB1 function and for selectively
enhancing CB2 actions in vivo. Our work will generate early candidates for the discovery and development of
new therapeutic medications. In this renewal, we will elucidate the functional selectivity aspect of CB1 agonists
and develop positive allosteric modulators at CB1 that selectively enhance endocannabinoid signaling. We also
propose to develop highly selective CB2 agonists to enable studies of CB2 in vivo while limiting the contributions
of CB1 that have been associated with undesirable side effects. Additionally, we propose to develop ligands
that act as activators of CB2 while also acting as CB1 antagonists. Using such compounds in vivo may lay the
groundwork for the development of medications for inflammatory and fibrotic disorders.
Our goals will be accomplished through the synthesis of druggable analogs. The design of these ligands will be
based on existing structures of the CB1 and CB2 receptors that were developed during the current funding period
and by utilizing computational approaches. The work will require detailed molecular pharmacology aimed at
studying the signaling of novel compounds accompanied by targeted mutations in CB1 and CB2 to confirm
mechanistic underpinnings of pharmacological divergences in signaling. The most efficient novel compounds
will be assayed using in vivo approaches aimed at exploring potential therapeutic value.
The overall project will provide foundational information on cannabinoid receptor signaling and serve as a basis
for the future development of rationally designed, mechanism-based therapeutic medications.

## Key facts

- **NIH application ID:** 10333992
- **Project number:** 2P01DA009158-20
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Alexandros Makriyannis
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,477,010
- **Award type:** 2
- **Project period:** 1994-09-30 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333992

## Citation

> US National Institutes of Health, RePORTER application 10333992, Endocannabinoid Active Sites as Therapeutic Targets (2P01DA009158-20). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10333992. Licensed CC0.

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