# CB1/CB2 Cannabinoid Ligands for HIV Neuropathic Pain

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2021 · $120,191

## Abstract

Abstract 
Many patients suffering from HIV will develop distal symmetrical neuropathy that is frequently accompanied by 
pain. In some patients, HIV antiretroviral treatments can elicit and exacerbate neuropathic pain. The mechanisms 
underlying HIV neuropathic pain (HIVNP) are not well understood. HIVNP is relatively resistant to treatments 
commonly used for other types of neuropathic pain (e.g., reuptake blockers, gabapentinoids). Clinically 
significant effects of smoked cannabis have been reported in HIVNP, suggesting that cannabinoid activity may 
provide significant analgesic benefit in these patients. First, we shall develop novel CB2 agonists with no or very 
low functional efficacy for CB1, with improved pharmacological profiles based on the AM1710 chemotype. These 
novel compounds will be potent CV2 agonists and neutral CB1 antagonists. The second approach will involve 
the design and synthesis of novel CB1/CB2 agonists that are peripherally acting. We shall seek to obtain novel 
compounds in which the CB2/CB1 contributions to their respective effects on HIVNP is optimized. We have 
shown that AM1710, a selective CB2 agonist developed in our laboratory, elicits analgesic actions in a model of 
HIVNP. We propose that CB2 agonists could prove to be an effective strategy for non-addictive treatment of 
HIVNP and possibly for other chronic pain conditions. We propose two approaches. Both approaches will 
develop novel ligands that encompass design controlled cannabinoid deactivation, a concept recently developed 
in our laboratory for cannabinergic compounds. This involves the introduction within each ligand of a serum 
esterase susceptible moiety, which when subjected to the enzyme’s hydrolytic action, transforms the molecule 
into inactive metabolites. The duration of action in vivo of the new compounds is controlled by the chemical 
nature and environment of the sessile group, as well as by the degree to which the novel compound is subject 
to a depot effect, a property largely controlled by the compound’s hydrophobic character. The project will involve 
1) the design and synthesis of the novel ligands and 2) in vitro characterization evaluation for their CB2 and CB1 
affinities and functional potencies, as well as their biochemical stabilities, or bioavailabilities, and abilities (or lack 
of) to cross the blood brain barrier. The successful compounds will be screened (Biochemical Core) for their 
effects in models of inflammatory pain. 3) A select number of compounds will be tested for their efficacy in a HIV 
neuropathic pain model for their side effects, tolerance, and potential abuse liability.

## Key facts

- **NIH application ID:** 10151592
- **Project number:** 5P01DA041307-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Alexandros Makriyannis
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $120,191
- **Award type:** 5
- **Project period:** 2017-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151592

## Citation

> US National Institutes of Health, RePORTER application 10151592, CB1/CB2 Cannabinoid Ligands for HIV Neuropathic Pain (5P01DA041307-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10151592. Licensed CC0.

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