Paul L. Prather, Ph.D.
Phone: (501) 686-5512
Ph.D. – University of Georgia, 1988
My research interests involve understanding the neurobiological mechanisms underlying the addictive states produced by drugs of abuse. Specifically, for over 20 years I have investigated the cellular and molecular mechanisms of signal transduction mediated by G-protein coupled receptors (GPCRs) with which drugs of abuse interact. In particular, the research focus of my laboratory involves the study of drugs of abuse that signal through opioid (m-, d- and k-) and cannabinoid (CB1 and CB2) receptors. My research has been funded from many sources, including grants from the NIH, private foundation awards, drug company contracts and intramural grants from UAMS.
One area of current research in my laboratory is based on our discovery that several monohydroxylated phase I metabolites of JWH-018 and JWH-073 (synthetic cannabinoids commonly observed in the emerging drug of abuse K2/Spice) retain high affinity and activity for both CB1 and CB2 receptors. Based on these observations, we propose that these metabolites exhibit unique properties and may act “in concert” to produce the distinct pharmacology and toxicity of synthetic K2 cannabinoids observed in human users. This project is currently funded by a R01 grant (DA039143) from the National Institute on Drug Abuse (NIDA).
A second long-term goal of my laboratory is to develop cannabinoid-based drugs that exhibit enhanced therapeutic efficacy with reduced adverse effects relative to currently available cannabinoid drugs. Toward this goal, we have recently characterized a novel class of indole quinulidione (IQD) analogues that exhibit high nanomolar affinity for CB1 receptors, a subset of which act as highly G-protein biased agonists. Due to this unique mechanism of action, these CB1 receptor agonists produce significantly less desensitization and down-regulation of CB1 receptors than a non-biased CB1 receptor agonist when administered chronically in vitro, and exhibit reduced tolerance development in mice following prolonged treatment. Therefore, a R01 grant (R01-GM125862) has been submitted to the NIGMS to test the hypothesis that this novel class of CB1 receptor agonists will produce fewer and less severe adverse effects when administered both acutely and chronically than therapeutically available cannabinoids.
Recent Research Support
National Institute on Drug Abuse R01-DA039143-A1 (05/01/16 – 04/30/21)
“Synthetic cannabinoid toxicity: Role of biotransformation”
Center for Clinical and Translational Research 2289-2 (CoI) (02/01/11 – 01/31/12)
“K2 in Arkansas: A Translational Public Health Response to an Emerging Drug of Abuse”
NININDS R21-NS058430-A1 (07/01/2008 – 06/30/2010)
“Selective CB2 cannabinoid agonists as candidate therapeutics for ALS therapy”
Ford, B.M., Franks, L.N., Tai, S., Fantegrossi, W.E., Wilson, C.D., Penthala, N.R., Crooks, P.A. and Prather, P.L, Characterization of Structurally Novel G Protein Biased CB1 Agonists: Implications for Drug Development., Pharmacol. Res. S1043-6618(16)31424-4, 2017 (PMID: 28838808)
Yadlapalli JSK, Dogra N, Walbaum AW, Wessinger WD, Prather PL, Crooks PA, Dobretsov M. Evaluation of Analgesia, Tolerance, and the Mechanism of Action of Morphine-6-O-Sulfate Across Multiple Pain Modalities in Sprague-Dawley Rats. Anesth Analg. doi: 10.1213/ANE.0000000000002006, 2017, (PMID: 28489639).
Ford BM, Tai S, Fantegrossi WE, Prather PL. Synthetic Pot: Not Your Grandfather’s Marijuana. Trends Pharmacol Sci. 38(3):257-276, 2017 (PMID: 28162792)
Franks LN, Ford BM, Prather PL. Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity. Front Pharmacol. 22;7:503, 2016 (PMID: 28066250)
Ford BM, Franks LN, Radominska-Pandya A, Prather PL. Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development. PLoS One. 11(12):e0167240, 2016 (PMID: 27936172)
Yadlapalli JS, Ford BM, Ketkar A, Wan A, Penthala NR, Eoff RL, Prather PL, Dobretsov M, Crooks PA. Antinociceptive effects of the 6-O-sulfate ester of morphine in normal and diabetic rats: Comparative role of mu- and delta-opioid receptors. Pharmacol Res. 113(Pt A):335-347, 2016 (PMID: 27637375)
Tai S, Hyatt WS, Gu C, Franks LN. Vasiljevik T, Brents LK, Prather PL, Fantegrossi WE. Repeated administration of phytocannabinoid Δ⁹-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. 103:22-32, 2015 (PMID: 26361728).
Anthony-Jalin AMA, Rajasekaran M, Prather PL, Kwon JS, Gajulapati CY, Kim C, Pahk K, Ju C, Kim WK. Non-selective cannabinoid receptor antagonists, hinokiresinols, reduce infiltration of microglia/macrophages into ischemic brain lesions in rat via modulating 2-arachidonolyglycerol-induced migration and mitochondrial activity. PLoS One. 10(10):e0141500, 2015 (PMID: 26517721).
Brents LK, Prather PL. The K2/Spice phenomenon: The emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products. Drug Metabolism Reviews. 46(1):72-85, 2014 (PMID: 24063277).
Fantegrossi WE, Moran JH, Radominska-Pandya A, Prather PL. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ⁹-THC: Mechanism underlying greater toxicity?, Life Sciences. 97:45-54, 2014 (PMID: 24084047).
Franks LN, Ford BM, Madadi NR, Penthala NR, Crooks PA, Prather PL. Characterization of the intrinsic activity for a novel class of indole quinuclidine analogs (IQDs) exhibiting high nanomolar affinity for CB1 and CB2 cannabinoid receptors., Eur J. Pharmacol. 737:140-148, 2014 (PMID: 24858620).
Marshell R, Kearney-Ramos T, Brents LK, Hyatt WS, Tai S, Prather PL, Fantegrossi WE. In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid ∆9-THC in mice: inhalation versus intraperitoneal injection., Pharmacol. Biochem. Behavior. 124:40-47, 2014 (PMID: 24857780).
Zheng J, Wang J, Loose DS, Prather PL,Hauer-Jensen M. Palmitoylethanolamide regulates radiation enteropathy development in a mast cell dependent manner., Digestive Diseases Sciences. 59(11):2693-2703, 2014 (PMID: 24848354).
Choi IY, Ju C, Anthony-Jalin AMA, Lee DI, Prather PL, Kim WK. Activation of CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. American Journal of Pathology. 182(3):928-939, 2013 (PMID: 23414569).
Ju C, Hwang S, Cho GS, Choi IY, Kondaji G, Choi Y, Prather PL, Kim WK. Differential anti-ischemic efficacy and therapeutic time window of trans– and cis-hinokiresinols: stereo-specific antioxidant and anti-inflammatory activities, Neuropharmacology. 67:465-475, 2013 (PMID: 23287539).
Madadi NR, Penthala NR, Brents LK, Ford BM, Prather PL, Crooks PA. Evaluation of (Z)-2-((1-benzyl-1H-indol-3-yl)methylene) quinuclidin-3-one analogues as novel high affinity ligands for CB1 and CB2 cannabinoid receptors., Bioorganic and Medicinal Chemistry Letters. 23(7):2019-21, 2013 (PMID: 23466226).
Rajasekaran M, Brents LK, Franks LN, Moran JH, Prather PL. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors., Toxicol. and Applied Pharmacol. 269(2):100-108, 2013 (PMID: 23537664).
Vasiljevik T, Franks LN, Ford BM, Prather PL, Fantegrossi WE, Prinsinzano TE. Design, synthesis and biological evaluation of aminoalkylindole derivatives as cannabinoid receptor ligands with potential for treatment of alcohol abuse., J. Med. Chem. 56(11):4537-4550, 2013 (PMID: 23631463).
Brents LK, Zimmerman SM, Saffell AR, Prather PL, Fantegrossi WE. Differential drug-drug interactions of the synthetic cannabinoids JWH-018 and JWH-073: Implications for drug abuse liability and pain therapy., J. Pharmacol. Exp. Ther. 346:350–361, 2013 (PMID: 23801678). **Highlighted paper in the September, 2013 issue of the Journal of Pharmacology and Experimental Therapeutics.
Seely KA, Patton AL, Moran CL, Prather PL, Fantegrossi WE, Radominska-Pandya A, Channell KB, Smith N, McCain KR, James LP, Moran JH. Forensic investigation of K2, Spice, and “bath salt” commercial preparations: A three-year study of new designer drug products containing synthetic cannabinoid, stimulant, and hallucinogenic compounds.”, and bath salt designer drugs, J. Forensic Sci. International. 233:416–422, 2013 (PMID: 24314548).
Prather PL, Francisdevaraj F, Dates C, Greer AK, Bratton Ford BM, Franks LN, Radominska-Pandya A. CB1 and CB2 receptors are novel molecular targets for tamoxifen and 4OH-tamoxifen., Biochem. Biophys. Res. Commun. 441(2): 339-343, 2013 (PMID: 24148245).
Brents LK, Medina-Bolivar LF, Seely KA, Nair V, Bratton SM, Nopo-Olabazal L, Patel RY, Liu H, Doerksen RJ, Prather PL, Radominska-Pandya A. Natural prenylated resveratrol analogs arachidin-1 and -3 demonstrate improved glucuronide profiles and have affinity for cannabinoid receptors., Xenobiotica. 42(2): 139-56, 2012 (PMID: 21970716).
Brents LK, Gallus-Zawada A, Radominska-Pandya A, Vasiljevik T, Prisinzano TE, Fantegrossi WE, Moran JH, Prather PL. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem. Pharmacol. 83(7):952-961, 2012 (PMID: 22266354).
Seely KA, Brents LK, Radominska-Pandya A, Endres GW, Keyes GS, Moran JH, Prather PL. A major glucuronidated metabolite of JWH-018 is a neutral antagonist at CB1 receptors. Chemical Research in Toxicology. 25(4):825-827, 2012 (PMID: 22404317).
Liu X, Jutooru I, Lei P, Kim KH, Lee SO, Brents LK, Prather PL, Safe SH. Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microrRNA-27a:ZBTB10 in breast cancer., Molecular Cancer Therapeutics. 11(7):1421-1431, 2012 (PMID: 22553354).
Seely KA, Brents LK, Franks LN, Rajasekaran M, Zimmerman SM, Fantegrossi WE, Prather PL. AM251 and rimonabant act as direct antagonists at mu-opioid receptors: Implications for opioid/cannabinoid interaction studies., Neuropharmacol. 63(5):905-915, 2012 (PMID: 22771770).
Chimalakonda KC, Seely KA, Bratton SM, Brents LK, Moran CL, Endres GW, James LP, Hollenberg PF, Prather PL, Radominska-Pandya A, Moran JH. Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: Identification of novel cannabinoid receptor ligands. Drug Metabolism and Disposition. 40(11):2174-2184, 2012 (PMID: 22904561).
Koryakina Y, Jones SM, Cornett LE, Seely KA, Brents LK, Prather PL, Kofman A, Kurten RC. The effects of the β-agonist isoproterenol on the down-regulation, functional responsiveness, and trafficking of the β2-adrenergic receptors with amino-terminal polymorphisms. Cell Biology International. 36(12):1171-1183, 2012 (PMID: 22938391).
Safe SH, Prather PL, Brents LK, Chadalapaka G, Jutooru I. Unifying mechanisms of action of the anticancer activities of triterpenoids and synthetic analogs. Anticancer Agents in Medicinal Chemistry, 12(10):1211-1220, 2012 (PMID: 22771770).