Position
Professor, Department of Pharmacology and Toxicology, College of Medicine
Contacts
- Phone: 501-686-5512
- Fax: 501-686-5521
- Email: PratherPaulL@uams.edu
Research Experience
Paul Prather, Ph.D., obtained a doctorate in pharmacology from the University of Georgia College of Pharmacy 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 UAMS College of Medicine in 1995. He was promoted to Associate Professor and granted tenure in 2002, with subsequent promotion to full professor in 2013. 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, Paul 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 National Institutes of Health, private foundation awards, drug company contracts and intramural grants from UAMS. He is currently funded until 2021 as the principal investigator of a R01 research 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 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 research grant (R01-GM125862) has been submitted to the National Institute of General Medical Sciences 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
Janganati V, Salazar P, Parks BJ, Gorman GS, Prather PL, Peterson EC, Alund
AW, Moran JH, Crooks PA, Brents LK. Deuterated buprenorphine retains
pharmacodynamic properties of buprenorphine and resists metabolism to the active metabolite norbuprenorphine in rats. Front Pharmacol. 2023 May 9;14:1123261. doi: 10.3389/fphar.2023.1123261. PMID: 37229250; PMCID: PMC10204800.
Crosby SV, Ahmed IY, Osborn LR, Wang Z, Schleiff MA, Fantegrossi WE, Nagar S, Prather PL, Boysen G, Miller GP. Similar 5F-APINACA Metabolism between CD-1 Mouse and Human Liver Microsomes Involves Different P450 Cytochromes. Metabolites. 2022 Aug 22;12(8):773. doi: 10.3390/metabo12080773. PMID: 36005645; PMCID: PMC9413144.
Shoeib AM, Benson LN, Mu S, MacMillan-Crow LA, Prather PL. Non-Canonical
Cannabinoid Receptors with Distinct Binding and Signaling Properties in Prostate and Other Cancer Cell Types Mediate Cell Death. Int J Mol Sci. 2022 Mar 11;23(6):3049. doi: 10.3390/ijms23063049. PMID: 35328467; PMCID: PMC8954350.
Cabanlong CV, Russell LN, Fantegrossi WE, Prather PL. Metabolites of
Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy
Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors.
Toxicol Sci. 2022 Apr 26;187(1):175-185. doi: 10.1093/toxsci/kfac024. PMID:
35201352; PMCID: PMC9216042.
Shoeib AM, Yarbrough AL, Ford BM, Franks LN, Urbaniak A, Hensley LL, Benson
LN, Mu S, Radominska-Pandya A, Prather PL. Characterization of cannabinoid
receptors expressed in Ewing sarcoma TC-71 and A-673 cells as potential targets for anti-cancer drug development. Life Sci. 2021 Nov 15;285:119993. doi: 10.1016/j.lfs.2021.119993. Epub 2021 Sep 28. PMID: 34592231; PMCID: PMC10395316.
Fulo HF, Shoeib A, Cabanlong CV, Williams AH, Zhan CG, Prather PL, Dudley GB.
Synthesis, Molecular Pharmacology, and Structure-Activity Relationships of
3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists. J Med Chem. 2021 May 13;64(9):6381-6396. doi: 10.1021/acs.jmedchem.1c00442. Epub 2021 Apr 23. PMID: 33887913; PMCID: PMC8683641.
Pinson AO, Pouncey DL, Schleiff MA, Fantegrossi WE, Prather PL, Radominska-
Pandya A, Boysen G, Miller GP. Significance of Competing Metabolic Pathways for 5F-APINACA Based on Quantitative Kinetics. Molecules. 2020 Oct 20;25(20):4820. doi: 10.3390/molecules25204820. PMID: 33092129; PMCID: PMC7587938.
Yang JF, Williams AH, Penthala NR, Prather PL, Crooks PA, Zhan CG. Binding
Modes and Selectivity of Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) Receptor Ligands. ACS Chem Neurosci. 2020 Oct 21;11(20):3455-3463. doi:
10.1021/acschemneuro.0c00551. Epub 2020 Sep 30. PMID: 32997485; PMCID:
PMC7756905.
Penthala NR, Shoeib A, Dachavaram SS, Cabanlong CV, Yang J, Zhan CG, Prather PL, Crooks PA. 7-Azaindolequinuclidinones (7-AIQD): A novel class of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands. Bioorg Med Chem Lett. 2020 Nov 15;30(22):127501. doi: 10.1016/j.bmcl.2020.127501. Epub 2020 Aug 31. PMID: 32882418; PMCID: PMC7686103.
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. Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity. Pharmacol Biochem Behav. 2020 Aug;195:172949. doi: 10.1016/j.pbb.2020.172949. Epub 2020 May 13. PMID: 32413436; PMCID: PMC7415729.
Jones S, Yarbrough AL, Fantegrossi WE, Prather PL, Bush JM, Radominska-
Pandya A, Fujiwara R. 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 Feb;8(1):e00561. doi: 10.1002/prp2.561. PMID: 32003945; PMCID: PMC6993754.