# In vitro and in vivo characterization of CB1 allosteric modulators

> **NIH NIH K01** · RESEARCH TRIANGLE INSTITUTE · 2020 · $168,429

## Abstract

The cannabinoid type-1 (CB1) receptor is a promising pharmacotherapeutic target for many diseases as
evidenced by a large body of preclinical and clinical data showing efficacy treating drug dependence/addiction,
pain, obesity/metabolic syndrome, and others. Unfortunately drugs developed that target the CB1 receptor either
directly or indirectly have had limited success, i.e. dronabinol produces undesired psychoactivity, rimonabant
produces depression/suicidal ideation, and PF-04457845 did not demonstrate efficacy. Important considerations
in the therapeutic vs. nontherapeutic effects of CB1 activation are the various signaling pathways that contribute
to either of these. Allosteric modulation provides an additional vector through which the CB1 receptor can be
manipulated for therapeutic gain. This study proposes to 1) examine novel structural analogs of established CB1
allosteric modulators for their ability to alter orthosteric ligand binding, function, and signaling bias; 2)
characterize G protein subtype-dependent coupling by orthosteric and allosteric ligands in N18TG2 cells which
provide physiologically relevant receptor/G protein stoichiometry; and 3) assess the effects of CB1 allosteric
modulators in assays of cannabinoid activity, opioid withdrawal and self-administration for determination of
efficacy in therapeutically relevant models. My goals for this career development award are to build on my
laboratory’s capabilities and prepare for independence as a principal investigator in the behavioral and molecular
pharmacology of drug abuse. My laboratory currently has the capabilities to carry out the proposed studies but I
require additional training in molecular pharmacology to learn G protein antibody capture scintillation proximity
assay to complete Aim 2 which I will learn in Dr. Allyn Howlett’s laboratory. I will also learn complementary
techniques in molecular biology in a workshop from New England BioLabs. I will also benefit from guidance in
receptor theory, application of allosteric models and quantification of signaling bias which I will receive from my
co-mentor Dr. Terry Kenakin. I also require training in self-administration for Aim 3 experiments which I will learn
in Dr. Jenny Wiley’s laboratory. In addition to technical training, I require career development in order prepare
for research independence. Under this award I will receive training in grantsmanship, laboratory management,
budget management, and responsible conduct of research. These career development activities will include one-on-one training with co-mentors as well as workshops to provide me with necessary training to successfully
compete for R01 funding and develop a highly productive and efficient independent research program.

## Key facts

- **NIH application ID:** 9961513
- **Project number:** 5K01DA045752-03
- **Recipient organization:** RESEARCH TRIANGLE INSTITUTE
- **Principal Investigator:** Thomas F Gamage
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,429
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961513

## Citation

> US National Institutes of Health, RePORTER application 9961513, In vitro and in vivo characterization of CB1 allosteric modulators (5K01DA045752-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9961513. Licensed CC0.

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