# Project 1 - Design and Synthesis of Novel Functionally Selective CB1 and CB2 Cannabinergic Ligands

> **NIH NIH P01** · NORTHEASTERN UNIVERSITY · 2024 · $625,740

## Abstract

OTHER PROJECT INFORMATION – SUMMARY/ABSTRACT
This project serves as the ligand development component of a comprehensive collaborative effort to
fundamentally expand our understanding of the selective and functional modulation of the two
cannabinoid receptors, CB1 and CB2. During the current funding period, we have made substantial progress in
exploring the functional and structural properties of CB1 and CB2 through the development of suitable
irreversible novel ligands. These have been used to obtain structural and functional information on CB1 and
CB2 through our Ligand Assisted Protein Structure (LAPS) approach. Results originating from LAPS were
further refined with the assistance of CB1 and CB2 X-ray and cryo-EM structures in complex with our high-affinity
ligands. Based on our early work we were successful in developing neutral CB1 receptor antagonists that are
being tested as potential medications for alcohol and opioid addiction (centrally active) as well as for pulmonary,
liver and kidney fibrotic conditions (peripherally active). We have made advances towards the goals of the
current cycle by distinguishing structural features of functional selectivity and developing functionally
selective ligands. Additionally, we have identified novel approaches for developing ligands with distinct
pharmacological profiles. These are now being integrated into our current submission. This project will provide
the basis for the development of ligands that are involved in the preferential modulation of CB1 and the
selective activation of CB2. We propose to accomplish our goals with the following specific aims: The first
aim encompasses the development of a) orthosteric agonists exhibiting functional selectivity for CB1 and b) CB1
positive allosteric modulators with irreversible binding characteristics. The second aim encompasses the
development of a) CB2 agonists with no or minimal efficacy for CB1 and b) bifunctional ligands that behave as
CB2 agonists/CB1 antagonists (Yin-Yang). The results and ligands produced under the auspices of this project
will serve as a basis for the development of novel medications with improved pharmacological profiles for
the treatment of addictive, inflammatory and fibrotic disorders.

## Key facts

- **NIH application ID:** 10846847
- **Project number:** 5P01DA009158-22
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Alexandros Makriyannis
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,740
- **Award type:** 5
- **Project period:** 1994-09-30 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846847

## Citation

> US National Institutes of Health, RePORTER application 10846847, Project 1 - Design and Synthesis of Novel Functionally Selective CB1 and CB2 Cannabinergic Ligands (5P01DA009158-22). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10846847. Licensed CC0.

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