Reduced Tolerance and Asymmetrical Crosstolerance to Effects of the Indole Quinuclidinone Analog PNR-4-20, a G Protein-Biased Cannabinoid 1 Receptor Agonist in Mice: Comparisons with Δ9-Tetrahydrocannabinol and JWH-018.
Benjamin M Ford, Christian V Cabanlong, Sherrica Tai, Lirit N Franks, Narsimha R Penthala, Peter A Crooks, Paul L Prather, William E Fantegrossi
Journal of Pharmacology and Experimental Therapeutics May 2019 DOI: 10.1124/jpet.118.252965 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Adult male National Institutes of Health Swiss mice |
| Interventions | PNR-4-20 Δ9-tetrahydrocannabinol (Δ9-THC) JWH-018 |
| Dose | PNR-4-20 100 mg/kg; Δ9-THC 30 mg/kg; JWH-018 3 mg/kg |
| Duration | Once per day for five consecutive days, followed by a drug abstinence period |
| Topics | Cannabis |
| Key points | The G protein-biased CB1R agonist PNR-4-20 produced less tolerance to hypothermic and cataleptic effects than unbiased agonists Δ9-THC and JWH-018, with full recovery after abstinence and less CB1R downregulation in hypothalamus and thalamus. The authors suggest IQD analogs warrant further investigation as a scaffold for new therapeutics. |
Abstract
Most cannabinoid 1 receptor (CB1R) agonists will signal through both G protein-dependent and -independent pathways in an unbiased manner. Recruitment of β-arrestin 2 desensitizes and internalizes receptors, producing tolerance that limits therapeutic utility of cannabinoids for chronic conditions. We developed the indole quinuclidinone (IQD) analog (Z)-2-((1-(4-fluorobenzyl)-1H-indol-3-yl)methylene)quinuclidin-3-one (PNR-4-20) as a novel G protein-biased agonist at CB1Rs, and the present studies determine if repeated administration of PNR-4-20 produces lesser tolerance to in vivo effects compared with unbiased CB1R agonists Δ9-tetrahydrocannabinol (Δ9-THC) and 1-pentyl-3-(1-naphthoyl)indole (JWH-018). Adult male National Institutes of Health Swiss mice were administered comparable doses of PNR-4-20 (100 mg/kg), Δ9-THC (30 mg/kg), or JWH-018 (3 mg/kg) once per day for five consecutive days to determine tolerance development to hypothermic, antinociceptive, and cataleptic effects. Persistence of tolerance was then determined after a drug abstinence period. We found that unbiased CB1R agonists Δ9-THC and JWH-018 produced similar tolerance to these effects, but lesser tolerance was observed with PNR-4-20 for hypothermic and cataleptic effects. Tolerance to the effects of PNR-4-20 completely recovered after drug abstinence, while residual tolerance was always observed with unbiased CB1R agonists. Repeated treatment with PNR-4-20 and Δ9-THC produced asymmetric crosstolerance to hypothermic effects. Importantly, binding studies suggest PNR-4-20 produced significantly less downregulation of CB1Rs relative to Δ9-THC in hypothalamus and thalamus of chronically treated mice. These studies suggest that the G protein-biased CB1R agonist PNR-4-20 produces significantly less tolerance than unbiased cannabinoid agonists, and that the IQD analogs should be investigated further as a novel molecular scaffold for development of new therapeutics.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 2
- Side-Chain Homologs of Δ9-THC, Δ8-THC, and HHC Reveal Pathway Bias at CB1R and CB2R Cannabinoid Receptors. Molecular Neurobiology August 20, 2026
- Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors. Toxicological sciences : an official journal of the Society of Toxicology April 26, 2022
Cites 4
- Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner. Pharmacological Research December 2015
- Cross-substitution of Δ9-tetrahydrocannabinol and JWH-018 in drug discrimination in rats. Pharmacology, Biochemistry, and Behavior September 2014
- β-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biological Psychiatry April 15, 2012
- Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One 2011