Paul Prather, Ph.D.

Position

Professor, Department of Pharmacology and Toxicology

Contacts

Phone: (501)-686-5512
FAX: (501)-686-5521
E-mail: PratherPaulL@uams.edu

Research Experience

Dr. Prather obtained a Ph.D. in Pharmacology from the College of Pharmacy at the University of Georgia in 1988. After completing two sequential postdoctoral positions at the University of North Texas Health Sciences Center and the University of Minnesota, he began a tenure-track position as an Assistant Professor in the Department of Pharmacology and Toxicology in the College of Medicine at UAMS in 1995. He was promoted to Associate Professor and granted tenure in 2002, with subsequent promotion to Full Professor in 2013. Dr. Prather is trained as a cellular and molecular pharmacologist whose research interests during the last 29 years have focused on understanding the neurobiological mechanisms of drugs of abuse.

Research Interests

Throughout his research career, Dr. Prather has 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 his laboratory involves the study of drugs of abuse that signal through opioid (m-, d- and k-) and cannabinoid (CB1 and CB2) receptors. His research has been funded from many sources, including grants from the NIH, private foundation awards, drug company contracts and intramural grants from UAMS. He is currently funded until 2021 as the Principal Investigator of a R01 grant awarded by the National Institute on Drug Abuse (R01-DA039143-A1) entitled “Synthetic cannabinoid toxicity: Role of biotransformation”.

One area of current research in his laboratory is based on the 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, his group has proposed 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.

A second long-term goal of Dr. Prather’s 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, his group has 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 Publications

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. 2017 Sep 29. doi: 10.1111/bph.14055. [Epub ahead of print] PubMed PMID: 28963716.

Ford BM, Franks LN, Tai S, Fantegrossi WE, Stahl EL, Berquist MD, Cabanlong CV, Wilson CD, Penthala NR, Crooks PA, Prather PL. Characterization of structurally novel G protein biased CB(1) agonists: Implications for drug development. Pharmacol Res. 2017 Aug 23;125(Pt B):161-177. doi:10.1016/j.phrs. 2017.08.008. [Epub ahead of print] PubMed PMID: 28838808.

Ford BM, Tai S, Fantegrossi WE, Prather PL. Synthetic Pot: Not Your Grandfather’s Marijuana. Trends Pharmacol Sci. 2017 Mar;38(3):257-276. doi: 10.1016/j.tips.2016.12.003. Epub 2017 Feb 2. Review. PubMed PMID: 28162792; PubMed Central PMCID: PMC5329767.

Franks LN, Ford BM, Prather PL. Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity. Front Pharmacol. 2016 Dec 22;7:503. doi: 10.3389/fphar.2016.00503. eCollection 2016. PubMed PMID: 28066250; PubMed Central PMCID: PMC5177629.

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. 2016 Dec 9;11(12):e0167240. doi: 10.1371/journal.pone.0167240. eCollection 2016. PubMed PMID: 27936172; PubMed Central PMCID: PMC5147891.

Tai S, Hyatt WS, Gu C, Franks LN, Vasiljevik T, Brents LK, Prather PL, Fantegrossi WE. 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. Pharmacol Res. 2015 Dec;102:22-32. doi: 10.1016/j.phrs.2015.09.006. Epub 2015 Sep 8. PubMed PMID: 26361728; PubMed Central PMCID: PMC4684449.

Franks LN, Ford BM, Madadi NR, Penthala NR, Crooks PA, Prather PL. Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs. Eur J Pharmacol. 2014 Aug 15;737:140-8. doi: 10.1016/j.ejphar.2014.05.007. Epub 2014 May 20. PubMed PMID: 24858620; PubMed Central PMCID: PMC4383465.

Prather PL, FrancisDevaraj F, Dates CR, Greer AK, Bratton SM, Ford BM, Franks LN, Radominska-Pandya A. CB1 and CB2 receptors are novel molecular targets for Tamoxifen and 4OH-Tamoxifen. Biochem Biophys Res Commun. 2013 Nov 15;441(2):339-43. doi: 10.1016/j.bbrc.2013.10.057. Epub 2013 Oct 19. PubMed PMID: 24148245; PubMed Central PMCID: PMC3860589.

Fantegrossi WE, Moran JH, Radominska-Pandya A, Prather PL. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC:  mechanism underlying greater toxicity? Life Sci. 2014 Feb 27;97(1):45-54. doi: 10.1016/j.lfs.2013.09.017. Epub 2013 Sep 29. Review. PubMed PMID: 24084047; PubMed Central PMCID: PMC3945037.

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 Appl Pharmacol. 2013 Jun 1;269(2):100-8. doi: 10.1016/j.taap.2013.03.012. Epub 2013 Mar 26. PubMed PMID: 23537664; PubMed Central PMCID: PMC3685885.

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. 2016 Nov;113(Pt A):335-347. doi: 10.1016/j.phrs.2016.09.012. Epub 2016 Sep 13. PubMed PMID: 27637375; PubMed Central PMCID: PMC5107169.

Vasiljevik T, Franks LN, Ford BM, Douglas JT, Prather PL, Fantegrossi WE, Prisinzano TE. Design, synthesis, and biological evaluation of aminoalkylindole derivatives as cannabinoid receptor ligands with potential for treatment of alcohol abuse. J Med Chem. 2013 Jun 13;56(11):4537-50. doi: 10.1021/jm400268b. Epub 2013 May 22. PubMed PMID: 23631463; PubMed Central PMCID: PMC3904296.

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. Chem Res Toxicol. 2012 Apr 16;25(4):825-7. doi: 10.1021/tx3000472. Epub 2012 Mar 15. PubMed PMID: 22404317; PubMed Central PMCID: PMC3921679.

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. 2012 Apr 1;83(7):952-61. doi: 10.1016/j.bcp.2012.01.004. Epub 2012 Jan 18. PubMed PMID: 22266354; PubMed Central PMCID: PMC3288656.

Brents LK, Reichard EE, Zimmerman SM, Moran JH, Fantegrossi WE, Prather PL. 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;6(7):e21917. doi: 10.1371/journal.pone.0021917. Epub 2011 Jul 6. PubMed PMID: 21755008; PubMed Central PMCID: PMC3130777.

Moran CL, Le VH, Chimalakonda KC, Smedley AL, Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski PJ, Wessinger WD, Fantegrossi WE, Prather PL, James LP, Radominska-Pandya A, Moran JH. Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine. Anal Chem. 2011 Jun 1;83(11):4228-36. doi: 10.1021/ac2005636. Epub 2011 May 6. PubMed PMID: 21506519; PubMed Central PMCID: PMC3105467.