Thomas Prisinzano Research

  • BS: Chemistry; University of Delaware, Newark, Delaware 1995
  • Ph.D.: Medicinal Chemistry; School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia. 2000
  • Postdoctoral: Organic and Medicinal Chemistry; National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland. 2000 - 2003
  • D. John Faulkner Award, American Society of Pharmacognosy (1st Recipient) 2005
  • Jack L. Beal Award, Journal of Natural Products 2007
  • Matt Suffness (Young Investigators) Award, American Society of Pharmacognosy 2008
  • Joseph Cochin Young Investigator Award, College on Problems of Drug Dependence 2011
  • David W. Robertson Award for Excellence in Medicinal Chemistry, American Chemical Society 2012

Psychoactive Natural Products

The opium poppy, Papaver somniferum, has been used for centuries for the relief of pain and to induce sleep. Among the most important constituents in opium are the alkaloids morphine and codeine. Many of the opiate agonists and antagonists derived from these alkaloids are essential for the effective practice of modern medicine. However, these compounds have undesirable side effects, such as tolerance, dependence, and respiratory depression. New drugs are needed with fewer side effects.

Morphine and related opiates exert their major pharmacological effects by interacting with opioid receptors in the central nervous system. Three types of opioid receptors (mu, kappa, and delta) have been identified and each has a role in the mediation of pain. As a consequence of target drug design and synthetic efforts, we have achieved a better understanding of opioid receptors. Moreover, these efforts have opened new avenues for chemical investigation.

Our research combines natural product isolation and medicinal chemistry and is based on the central hypothesis that structural modification of natural products will lead to the identification of novel agonists and antagonists at CNS receptors. Identification of these new ligands is expected to lead to potential new medications for the treatment of drug dependence, as well as, new tools for chemical biology.

  • Tidgewell K, Groer CE, Harding WW, Lozama A, Schmidt M, Marquam A, Hiemstra J, Dersch CM, Partilla JS, Rothman RB, Bohn LM, Prisinzano TE. Herkinorin analogues with differential beta-arrestin-2 interactions. J Med Chem. 2008;51:2421-2431.
  • Prisinzano TE and Rothman RB. Salvinorin A analogs as probes in opioid pharmacology. Chem Rev. 2008;108:1732-1743.
  • Rothman RB, Baumann MH, Prisinzano TE, Newman AH. Dopamine transport inhibitors based on GBR12909 and Benztropine as potential medications to treat cocaine abuse. Biochem Pharmacol. 2008;75:2-16.
  • Simpson DS, Katavic PL, Lozama A, Harding WW, Parrish D, Deschamps JR, Dersch CM, Partilla JS, Rothman RB, Navarro H, Prisinzano TE. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: synthesis and opioid receptor activity of salvinicin analogues. J. Med. Chem. 2007; 50:3596.
  • Groer CE, Tidgewell K, Moyer RA, Harding WW, Rothman RB, Prisinzano TE, Bohn LM. An Opioid Agonist that Does Not Induce Mu Opioid Receptor – Arrestin Interactions or Receptor Internalization. Mol. Pharmacol. 2007;71:549-557.
  • Rothman RB, Murphy D, Dersch CM, Partilla JS, Xu H, Schmidt M, Tidgewell K, Prisinzano TE. Salvinorin A: Allosteric Interactions at the Mu Opioid Receptor. J. Pharmacol. Exp. Ther. 2007;320:801-810.
  • Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov Y, Kreek MJ. Effects of salvinorin A, a k-opioid hallucinogen, on a neuroendocrine biomarker assay in non-human primates with high k-receptor homology to humans. J Pharmacol Exp Ther. 2007;320:300-306.
  • Xu H, Partilla JS, Wang X, Rutherford JM, Tidgewell K, Prisinzano TE, Bohn LM, Rothman RB. A Comparison of Non-internalizing (Herkinorin) and Internalizing (DAMGO) m Opioid Agonists on Cellular Markers of Opioid Tolerance and Dependence. Synapse 2007;61:166-175.
  • Fink BD, O’Malley Y, Ross NC, Prisinzano TE, Sivitz WI. Reactive Oxygen and Targeted Antioxidant Administration in Endothelial Cell Mitochondria. J Biol Chem. 2006;281:39766-39775.
  • Tidgewell K, Harding WW, Lozama A, Cobb H, Shah K, Kannan P, Dersch CM, Parish D, Deschamps JR, Rothman RB, Prisinzano TE. Synthesis of Salvinorin A Analogues as Opioid Receptor Probes. J Nat Prod. 2006;69:914-918.
  • Vyas, P. M.; Roychowdhury, S.; Khan, F. D.; Prisinzano, T. E.; Lamba, J. K.; Schuetz, E. G.; Blaisdell, J.; Goldstein, J. A.; Munson, K. L.; Hines, R. N.; Svensson, C. K. Enzyme-mediated protein haptenation of dapsone and sulfamethoxaozle in human keratinocytes - 1. Expression and role of cytochromes P450. J. Pharmacol. Exp. Ther. 2006, 319, 488-496.
  • Chemuturi, N.V.; Haraldsson, J. E.; Prisinzano, T. E.; Donovan, M. D. Role of Dopamine Transporter (DAT) in Dopamine Transport across the Bovine Nasal Mucosa. Life Sci. 2006, 79, 1391-1398.
  • Harding, W. W.; Schmidt, M.; Tidgewell, K.; Kannan, P.; Holden, K. G.; Dersch, C. M.; Rothman, R. B.; Prisinzano, T. E. Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Selective Modification of the Furan Ring. Bioorg. Med. Chem. Lett. 2006, 16, 3170-3174.
  • Harding, W. W.; Schmidt, M.; Tidgewell, K.; Kannan, P.; Holden, K. G.; Gilmour, B.; Navarro, H.; Rothman, R. B.; Prisinzano, T. E. Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Semisynthesis of Salvinicin A and B and Other Chemical Transformations of Salvinorin A. J. Nat. Prod. 2006, 69, 107-112.
  • Sulima, A.; Prisinzano, T. E.; Jacobson, A. E.; Rice, K. C.; Spande, T.; Whitaker, N.; Deschamps, J. R.; Hochberg, Z. A Concise Method for the Preparation of Deuterium-labeled Cortisone: Synthesis of [6,7-2H]Cortisone. Steroids 2005, 70, 763-769.
  • Schmidt, M. S.; Prisinzano, T. E.; Tidgewell, K.; Harding, W. W.; Butelman, E. R.; Murry, D. J. Determination of Salvinorin A in Body Fluids by High Performance Liquid Chromatography-Atmospheric Pressure Chemical Ionization. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2005, 818, 221-225.
  • Harding, W. W.; Tidgewell, K.; Byrd, N.; Cobb, H.; Dersch, C. M.; Butelman, E. R.; Rothman, R. B.; Prisinzano, T. E. Neoclerodane Diterpenes as a Novel Scaffold for Mu Opioid Receptor Ligands. J. Med. Chem. 2005, 48, 4765-4771.
  • Harding, W. W.; Hodge, M.; Wang, Z.; Woolverton, W. L.; Parrish, D.; Deschamps, J. R.; Prisinzano, T. E. Enantioselective Synthesis of (R,R)- and (S,S)-2-[(3-Chlorophenyl)-(2-methoxyphenoxy)methyl]morpholine Tetrahedron: Asymmetr. 2005, 16, 2249-2256.
  • Harding, W. W.; Tidgewell, K.; Schmidt, M.; Shah, K.; Dersch, C. M.; Synder, J.; Parrish, D.; Deschamps, J. R.; Rothman, R. B.; Prisinzano, T. E. Salvinicin A and B, New Neoclerodane Diterpenes from Salvia divinorum. Org. Lett. 2005, 7, 3017-3020.
  • Prisinzano, T., Rice, K. C., Baumann, M., Rothman, R. B.: Development of Neurochemical Normalization (“Agonist Substitution”) Therapeutics for Stimulant Abuse: Focus on the Dopamine Uptake Inhibitor, GBR12909. Curr. Med. Chem. CNS Agents 2004, 4, 47-59
  • Prisinzano T, Podobinski J, Tidgewell K, Luo M, Swenson D. Synthesis and determination of the absolute configuration of the enantiomers of modafinil. Tetrahedron: Asymmetr. 2004, 15, 1053-1059.
  • Tidgewell K, Harding WW, Schmidt M, Holden KG, Murry DJ, Prisinzano TE. A facile method for the preparation of deuterium labeled salvinorin A: synthesis of [2,2,2- 2 H 3 ]-salvinorin A. Bioorg Med Chem Lett. 2004, 14, 5099-5102.
  • Osorio-Lozada A, Prisinzano T, Olivo HF. Synthesis and determination of the absolute stereochemistry of the enantiomers of the psychostimulant drugs modafinil and adrafinil. Tetrahedron: Asymmetr. 2004, 14, 3811-3815.
  • Greiner, E., Prisinzano, T., Johnson II, E. M., Dersch, C. M., Marcus, J., Partilla, J. S., Rothman, R. B., Jacobson, A. E., Rice, K. C.: Structure-Activity Relationship Studies of Highly Selective Inhibitors of the Dopamine Transporter: N-Benzyl Piperidine Analogues of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909). J. Med. Chem. 2003, 46, 1465-1469.
  • Rothman, R. B., Jayanthi, S., Dersch, C. M., Cadet, J. L., Prisinzano, T., Rice, K. C., Baumann, M. H.: Fenfluramine Administration to Rats According to a “Neurotoxic” Protocol Decreases Serotonin Transporter Binding, but not Serotonin Transporter Protein. Synapse 2003, 50, 233-239.
  • Yu, H., Prisinzano, T., Rothman, R. B., Dersch, C. M., Horel, R., Marcus, J., Jacobson, A. E., Rice, K. C.: Synthesis and Biological Activity of 8beta-Substituted Hydrocodone Indole and Hydromorphone Indole Derivatives. Bioorg. Med. Chem. Lett. 2002, 12, 165-168.
  • Prisinzano, T., Greiner, E., Johnson II, E. M., Dersch, C. M., Marcus, J., Partilla, J. S., Rothman, R. B., Jacobson, A. E., Rice, K. C.: Piperidine Analogues of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909): High Affinity Ligands for the Dopamine Transporter. J. Med. Chem. 2002, 45, 4371-4374.
  • Law, H., Dukat, M., Teitler, M., Lee, D. K. H., Mazzocco, L., Kamboj, R., Rampersad, V., Prisinzano, T., Glennon, R. A.: Benzylimidazolines as h5-HT1B/1D Serotonin Receptor Ligands: A Structure-Affinity Investigation. J. Med. Chem. 1998, 41, 2243-2251.

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