Project Overview

The Challenge: Current therapies for treating a number of mental health disorders – depression, anxiety,
and PTSD, among them – adequately treat only a small fraction of afflicted patients. Promising new targets,
despite strong rationales, have not improved this picture. As ketamine provided more than two decades ago,
a breakthrough is needed that will dramatically shift the paradigm of care. The clinical utility that the
psychedelics are now experiencing has led to their resurgence as a legitimate area for study and there is
growing interest in their practical utility. Broader use will, however, depend on an expanded safety margin
with respect to the undesirable hallucinogenic effects; progress here will only come in the form of NCEs.

The Solution: G protein-coupled receptors (GPCRs) respond to a wide variety of stimuli – neurotransmitters,
lipids, hormonal peptides, proteins, extracellular calcium, proteases to name only the most common.
Localized in cell membranes, they act at the interface between the extracellular and intracellular milieu with
additional functions on distinct intracellular organelles. Binding of agonist molecules to GPCRs leads to
coupling of downstream cellular effectors that modulate levels of key second messengers, responsible for
diverse cellular responses. Overlooked until recently, GPCRs are recognized as engaging not one but
multiple downstream signaling effectors. This notion of functional selectivity has led to a richer appreciation
of GPCRs as a target whereby selective effectors can be modulated in a pathway-specific manner. As such,
GPCRs will represent the cornerstone of a ligand screening system, to be developed as described in this
proposal, that will be instrumental in the identification of new chemical entities (NCEs) with the potential to
treat mental health disorders.

Expected Achievements/Impact: Psychedelic-based approaches that leverage selective signaling
pathways are expected to deliver clinical efficacy without the induction of hallucinogenic effects. Work to date
suggests that understanding the diversity of GPCR function can serve as a valid starting point for a screening
platform, thus unlocking its potential to deliver novel therapeutics. This proposal provides strong potential
benefits to patients with mental health disorders and important training activities for students.

Principal Investigator

Terence Hébert , McGill University

Team Members

Paul Clarke, McGill University

Graciela Pineyro, Université de Montréal

Peter Chidiac, Western University

Partners and Donors

CQDM

Diamond Therapeutics