University of Arkansas for Medical Sciences Logo University of Arkansas for Medical Sciences
College of Medicine: Department of Pharmacology and Toxicology

Paul L. Prather, Ph.D.

Prather

Professor
Phone: 501-686-5512
Fax: 501-686-5510
Email: pratherpaull@uams.edu

Education

Ph.D. – University of Georgia, 1988

Research Interests

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.

Meet Dr. Prather’s Research Team

Recent Research Support

Current Research

  • R21-DA049585 NIDA (CoI )(07/01/19-06/21/21
    “Use of precision deuteration to determine the contribution of norbuprenorphine to buprenorphine-associated neonatal abstinence syndrome.”
  • T32-GM106999 NIGMS  (Program Director) (07/01/13-06/30/23)
    “Systems pharmacology and toxicology training program.”
  • T32-DA022981 NIDA  (Program Faculty Member) (06/01/12-06/30/22)
    “Translational training in addiction.”
  • R01-DA039143-02s1-2 NIH/NOA (PI)  (05/01/16 – 04/30/21)
    “Synthetic cannabinoid toxicity: Role of biotransformation.”

Completed Research

  • 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”
  • R21-NS058430-A1 NININDS (07/01/2008 – 06/30/2010)
    “Selective CB2 cannabinoid agonists as candidate therapeutics for ALS therapy”

Publications

  • Penthala, NR., Shoeib, A, Dachavaram, SS., Cabanlong, CV, Yang, J., Zhan, CG, Prather, PL. and Crooks, P.A., 7-Azaindolequinuclidinones (7-AIQD): A novel class of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands., Bioorganic and Medicinal Chemistry Letters, 30(22):127501, 2020..
  • Jing-Fang, Y., Williams, A., Penthala, NR, Prather, PL, Crooks, PA. and Zhan, CG, Binding modes and selectivity of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands., ACS Chemical Neuroscience, September 30, 2020, doi: 10.1021/acschemneuro.0c00551. Online ahead of print. PMID: 32997485.
  • Pinson A, Yarbrough AL, Bush JM, Cabanlong CV, Shoeib A, Jackson BK, Fukuda S, Gogoi J, Fantegrossi WE, McCain K, Prather PL, Fujiwara R, Radominska-Pandya A.Pinson A, et al. Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity. Pharmacol Biochem Behav. ;195: 172949. 2020 doi: 10.1016/j.pbb.2020.172949. Online ahead of print.Pharmacol Biochem Behav. 2020.PMID: 32413436
  • Jones S, Yarbrough AL, Fantegrossi WE, Prather PL, Bush JM, Radominska-Pandya A, Fujiwara R.Jones S, et al. Identifying cytochrome P450s involved in oxidative metabolism of synthetic cannabinoid N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide (STS-135). Pharmacol Res Perspect. 2020 ;8(1):e00561. doi: 10.1002/prp2.561.Pharmacol Res Perspect. 2020. PMID: 32003945; PMCID: PMC6993754
  • Ford BM, Cabanlong CV, Tai S, Franks LN, Penthala NR, Crooks PA, Prather PL, Fantegrossi WE.Ford BM, et al.J Pharmacol Exp Ther. 2019 ;369(2):259-269. doi: 10.1124/jpet.118.252965. Epub 2019 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. J Pharmacol Exp Ther. 2019.PMID: 30833484; PMCID: PMC6447997
  • Jones S, Yarbrough AL, Shoeib A, Bush JM, Fantegrossi WE, Prather PL, Radominska-Pandya A, Fujiwara R.Jones S, et al. Enzymatic analysis of glucuronidation of synthetic cannabinoid 1-naphthyl 1-(4-fluorobenzyl)-1H-indole-3-carboxylate (FDU-PB-22). Xenobiotica. 2019 ;49(12):1388-1395. doi: 10.1080/00498254.2019.1580403. Epub 2019 Xenobiotica. 2019.PMID: 30739533; PMCID :PMC7133092
  • Hutchison RD, Ford BM, Franks LN, Wilson CD, Yarbrough AL, Fujiwara R, Su MK, Fernandez D, James LP, Moran JH, Patton AL, Fantegrossi WE, Radominska-Pandya A, Prather PL.Hutchison RD, et al. Atypical Pharmacodynamic Properties and Metabolic Profile of the Abused Synthetic Cannabinoid AB-PINACA: Potential Contribution to Pronounced Adverse Effects Relative to Δ9-THC. Front Pharmacol. 2018 26;9:1084. doi: 10.3389/fphar.2018.01084. eCollection 2018.Front Pharmacol. 2018.PMID: 30319418; PMCID; PMC6168621
  • Franks LN, Ford BM, Fujiwara T, Zhao H, Prather PL. The tamoxifen derivative ridaifen-B is a high affinity selective CB2 receptor inverse agonist exhibiting anti-inflammatory and anti-osteoclastogenic effects. Toxicol Appl Pharmacol.  353:31-42, 2018. PMID: 29906493
  • Patton AL, Seely KA, Yarbrough AL, Fantegrossi W, James LP, McCain KR, Fujiwara R, Prather PL, Moran JH, Radominska-Pandya A. Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants. Biochem Biophys Res Commun. 498(3):597-602, 2018 PMID: 29522717
  • Yadlapalli JSK, Dogra N, Walbaum AW, Prather PL, Crooks PA, Dobretsov M. Pinprick hypo- and hyperalgesia in diabetic rats: Can diet content affect experimental outcome? Neurosci Lett. 673:24-27, 2018. PMID: 29490230
  • Prather PL. Preface to DMR special edition ‘Cannabinoid receptors and ligands: therapeutic drug development and abuse potential’. Drug Metab Rev.  50(1):1-2, 2018. PMID: 29378464
  • Yadlapalli JSK, Dogra N, Walbaum AW, Prather PL, Crooks PA, Dobretsov M. Preclinical assessment of utility of M6S for multimodal acute and chronic pain treatment in diabetic neuropathy. Life Sci. 192:151-159, 2018. PMID: 9191644
  • Crowe MS, Wilson CD, Leishman E, Prather PL, Bradshaw HB, Banks ML, Kinsey SG.The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice. Br J Pharmacol. 174(23):4523-4539, 2017. PMID: 28963716
  • 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

View Dr. Prathers’ Publication List