Raymond G. Booth Ph.D.
Professor
Education
B.S., Pharmacy, Northeastern University, Boston, MA (1983)
Ph.D., Pharmaceutical Chemistry, University of California at San Francisco (1988)
Postdoctoral Fellowship in Neuroscience, Harvard Medical School, Boston, MA (1988 - 90)
Research Expertise
The lab uses experimental approaches that integrate the fields of medicinal chemistry (targeted ligand synthesis, 3-D QSAR computational chemistry, molecular modeling) and molecular pharmacology (in vitro affinity and functional studies, mutagenesis studies, in vivo pharmacotherapy studies). General goals of the research are to develop drugs targeting brain neurotransmitter G protein-coupled receptors (GPCRs) with pharmacotherapeutic relevance in neurodegenerative disorders (e.g., Parkinson’s and Alzheimer’s disease) and neuropsychiatric disorders (e.g., schizophrenia, drug addiction, depression, neuroses, eating disorders).
Current Research
Drug Design Targeting Brain Neurotransmitter GPCRs
G protein-coupled receptors (GPCRs) are membrane-bound proteins that are the receptors for several brain neurotransmitters, including, acetylcholine, histamine, and serotonin, that are important in the pathophysiology and pharmacotherapy of neuropsychiatric disorders (schizophrenia, anxiety, depression, addiction, eating disorders) and neurodegenerative disorders (Alzheimer’s and Parkinson’s disease). Our laboratory focuses on the design and synthesis of drugs targeting brain acetylcholine, histamine, and serotonin GPCRs, as well as, the molecular pharmacological and structural characterization of these neurotransmitter receptors. Current research programs include development of drug molecules targeting serotonin 5HT2-type GPCRs that have shown in vivo pharmacotherapeutic activity for schizophrenia, obesity, and cocaine addiction. We also have synthesized molecules targeting brain histamine H1 GPCRs that show in vivo activity relevant to Parkinson’s disease pharmacotherapy, and, we are developing drugs active at acetylcholine muscarinic-type GPCRs for Alzheimer’s disease and drug addiction. These research programs generally include synthetic medicinal chemistry approaches to obtain novel compounds, in vitro molecular pharmacological studies, computational chemistry and molecular modeling studies toward GPCR structural determination and optimization of drug chemistry, and, in vivo pharmacotherapy studies in laboratory rodents.
GPCR Functional Selectivity and Oligomerization
Another area of research concerns characterization of the molecular ligand–receptor structural events involved in ligand-directed signaling associated with activation of GPCRs. This phenomenon, sometimes referred to as ligand functional selectivity, accounts for the multiplicity of therapeutic effects and untoward side effects associated with pharmacotherapy of many brain and peripheral disorders. Current research is aimed at synthesis of molecules that selectively activate specific G proteins and signal transduction pathways associated with brain acetylcholine, histamine, and serotonin GPCRs. Other experiments focus on characterizing ligand interaction with GPCR monomers versus oligomers – current evidence suggests that different functional effects and therapeutic outcomes may be associated with drug agonism or inverse agonism at histamine H1 GPCR monomers vs. oligomers.
Environmental Neurotoxicants
The laboratory also conducts studies to characterize the molecular mechanisms of bioactivation of environmental and endogenous compounds relevant to the pathophysiology of Parkinson’s disease.
Publications
Rowland NE, Crump EM, Nguyen N, Robertson K, Sun Z, Booth RG.
Booth RG, Fang L, Wilczynski A, Sivendren S, Sun Z, Travers S, Bruysters M,
Sansuk K, Leurs R. Molecular determinants of ligand-directed signaling for
the histamine H(1) receptor. Inflammation Research 57:40-44 (2008).
Sansuk K, Balog CI, van der Does AM, Booth RG, de Grip WJ, Deelder AM,
Bakker RA, Leurs R, Hensbergen PJ. GPCR Proteomics: Mass Spectrometric
and Functional Analysis of Histamine H1 Receptor after
Baculovirus-Driven and in Vitro Cell Free Expression. Journal of
Proteome Research 7:621-629 (2008).
Booth RG, Moniri NH. Novel Ligands Stabilize Stereo-Selective
Conformations of the Histamine H1 Receptor to Activate Catecholamine
Synthesis. Inflammation Research 56:1-12 (2007).
Booth, R.G. Psychotherapeutic Drugs: Chapter 22: Antipsychotic and
Anxiolytic Agents. In Foye's Principals of Medicinal Chemistry 6th
Edition (Lemke et al., eds) Williams and Wilkins, Baltimore; pp. 601-630
(2007).
Booth, R.G.. Chapter 25: Drugs used to treat neuromuscular disorders:
Antiparkinsonian and Spasmolytic Agents. In Foye's Principals of
Medicinal Chemistry 6th Edition (Lemke et al., eds) Lippincott Williams and
Wilkins, Baltimore; pp. 679-697 (2007).
Moniri NH, Booth RG. Role of PKA and PKC in Histamine H1
Receptor-Mediated Activation of Tyrosine Hydroxylase and Catecholamine
Synthesis in Mammalian Brain and Adrenal Tissues. Neuroscience
407:249-253 (2006).
Ghoneim OM, Legere JA, Golbraikh A, Tropsha A, Booth RG. Novel ligands
for the human histamine H1 receptor: Synthesis, pharmacology, and
comparative molecular field analysis studies of
2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes. Bioorganic
and Medicinal Chemistry, 14:6640-6658 (2006).
Booth RG, Moniri NH. Ligand-directed multifunctional signaling of histamine H1 receptors Inflammation Research 54: S44-45 (2005).
Heinzen EL, Booth RG, Pollack GM. Neuronal nitric oxide modulates morphine antinociceptive tolerance by enhancing constitutive activity of the µ-opioid receptor. Biochemical Pharmacology, 69:679-688 (2005).
Moniri NH, Booth RG. Functional heterogeneity of histamine H1 receptors. Inflammation Research 53:71-73 (2004)
Bakker RA, Dees G, Carrillo JJ, Booth RG, López-Gimenez JF, Graeme Milligan G, Strange PG, Leurs R. Domain swapping in the human histamine H1 receptor. Journal of Pharmacology and Experimental Therapeutics, 311:131-138 (2004).
Moniri NH, Covington-Strachan D, Booth RG. Ligand-directed functional heterogeneity of histamine H1 receptors: Novel dual-function ligands selectively activate and block H1-meditated phospholipas C and adenylyl cyclase signaling. Journal of Pharmacology and Experimental Therapeutics, 311:274-281 (2004).
Neumeyer, JL. Baldessarini, RJ. Booth, RG. Chapter 12, Therapeutic and diagnostic agents for Parkinson’s disease. In: Burgers’ Medicinal Chemistry and Drug Discovery, Sixth Edition, Donald J. Abraham (Ed), John Wiley and Sons, New York, pp 711-741 (2003).
Mottola, D., Kilts, J., Lewis, M., Smith, H., Walker, Q.D., Jones, S., Booth, R.G., Hyslop, D., Piercey, M., Wightman, M., Lawler, C., Nichols, D.E., and Mailman, R.B. Functional selectivity of dihydrexidine: I. Selective activation of post-synaptic dopamine D2 receptors linked to adenylate cyclase. Journal of Pharmacology and Experimental Therapeutics 301:1166-1178 (2002).
Booth RG, Moniri NH, Bakker RA, Choksi NY, Timmerman H, and Leurs R. A novel phenylaminotetralin radioligand reveals a sub-population of histamine H1 receptors. Journal of Pharmacology and Experimental Therapeutics 302:328-336 (2002).
Booth, R.G. and Neumeyer, J.L. Psychotherapeutic Drugs: Chapter 17: Antipsychotic and Anxiolytic Agents. In Foye’s Principals of Medicinal Chemistry 5th Edition (Lemke et al.,eds) Williams and Wilkins, Baltimore; pp. 408-434 (2002).
Booth, R.G. and Neumeyer, J.L. Chapter 20: Drugs used to treat neuromuscular disorders: Antiparkinsonian and Spasmolytic Agents. In Foye’s Principals of Medicinal Chemistry 5th Edition (Lemke et al.,eds) Williams and Wilkins, Baltimore; pp. 480-497 (2002).
Choksi, N.Y., Nix, William B., Wyrick, S.D., and Booth, R.G. A novel phenylaminotetralin recognizes histamine H1 receptors and stimulates dopamine synthesis in vivo in rat brain. Brain Research 852:151-160 (2000).
Bucholtz, E.C., Brown., R.L., Tropsha, A., Booth, R.G, and Wyrick, S.D. Synthesis, Evaluation and Comparative Molecular Field Analysis of 1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as Ligands for Histamine H1 Receptors. Journal of Medicinal Chemsitry.42:3041-3054(1999).
Booth, R.G., Owens, C.E., Brown, R.L., Bucholtz, E.C., Lawler, C.P., and Wyrick, S.D. Putative ?3 sites in mammalian brain have histamine H1 receptor properties: Evidence from ligand binding and distribution studies with the novel H1 radioligand [3H]-(-)-trans-1-phenyl-3-aminotetralin (PAT). Brain Research 837:95-105 (1999).
Bucholtz, E.C., Wyrick, S.D., Owens, C.E., and Booth, R.G. 1-Phenyl-3-dimethylaminotetralins (PATs): Effect of stereochemistry on binding and function at brain histamine receptors. Medicinal Chemistry Research 8:322-332 (1998).
Choksi, N.Y., Hussain, A., and Booth, R.G. 2-Phenylaminoadenosine stimulates dopamine synthesis in rat forebrain in vitro and in vivo via adenosine A2 receptors. Brain Research 761:151-155 (1997).
Choksi, N.Y., Kodavanti, P.R.S., Tilson, H.A., and Booth, R.G. Effects of Polychlorinated Biphenyls (PCBs) on Brain Tyrosine Hydroxylase Activity and Dopamine Synthesis in Rats. Fundamentals of Applied Toxicology 39:76-80 (1997)
Nickell, W. Ward, H.E., and Booth, R.G. Antianxiety agents. In Burger’s Medicinal Chemistry and Drug Discovery, 5th Edition, Volume 5 (Manfred E. Wolff, ed.) John Wiley and Sons, New York, 153-194 (1997).
Neumeyer, J.L and Booth, R.G. Chapter 12: Neuroleptics and anxiolytic agents. In Principles of Medicinal Chemistry 4th. Edition (William O. Foye, ed.) Lea Febiger, Philadelphia, 199-231 (1996).
Neumeyer, J.L and Booth, R.G. Chapter 13: Drugs used to treat neuromuscular disorders. In Principles of Medicinal Chemistry 4th. Edition (William O. Foye, ed.) Lea Febiger, Philadelphia, 232-246 (1996).
Neumeyer, J.L and Booth, R.G. Chapter 42: Pesticides. In Principles of Medicinal Chemistry 4th. Edition (William O. Foye, ed.) Lea Febiger, Philadelphia, 908-926 (1996).
Myers, A.M., Charifson, P.S., Owens, C.E., Kula, N.S., Baldessarini, R.J., McPhail, A.T., Booth, R.G., and Wyrick, S.D. Conformational analyses, pharmacophore identification, and comparative, molecular field analyses of ligands for the neuromodulatory ?3 receptor. Journal of Medicinal Chemistry 37:4109-4117 (1995).
Wyrick, S.D. and Booth, R.G. Progress in sigma receptor research. Drugs of the Future 20:1033-1044 (1995).
Wyrick, S.D., Booth, R.G., Myers, A.M., Owens, C.E., Bucholtz, E.C., Hooper, P.C., Kula, N.S., Baldessarini, R.J., and Mailman, R.B. 1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and related derivatives as ligands for the neuromodulatory ?3 receptor: Further structure-activity relationships. Journal of Medicinal Chemistry 38:3857-3864 (1995).
Wyrick, S.D., Myers, A.M., Booth, R.G., Kula, N.S., Baldessarini, R.J., and Mailman, R.B. Synthesis of [N-C3H3]-trans-(1R,3S)-(–)-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydro-naphthalene (H2-PAT). Journal of Labeled Compounds and Radiopharmaceuticals 34: 131-134 (1994).
Booth, R.G., Baldessarini, R.J., Owens, C.E., and Marsh, E. Actions of 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on dopamine synthesis in limbic and extrapyramidal regions of rat brain. Brain Research 662:283-288 (1994).
Booth, R.G., and Wyrick, S.D. Development of phenylaminotetralin ligands for a novel sigma (?3) receptor in brain. Medicinal Chemistry Research 4:225-237 (1994).
Wyrick, S.D., Booth, R.G., Myers, A.M., Owens, C.E., Kula, N.S., Baldessarini, R.J, Mailman, R.B., Synthesis and pharmacological evaluation of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for a novel receptor with sigma-like neuromodulatory activity. Journal of Medicinal Chemistry 36: 2542-2551 (1993).
Booth, R.G., Wyrick, S.D., Baldessarini, R.J., Kula, N.S., Myers, A.M., and Mailman, R.B. A new sigma-like receptor recognized by novel phenylaminotetralins: Ligand binding and functional studies Molecular Pharmacology 44: 1232-1239 (1993).
Teicher, M.H., Gallitano, A.L., Gelbard, H.A., Evans, H.K., Marsh, E.R., Booth, R.G., and Baldessarini, R.J. Dopamine D1 autoreceptor function: Possible expression in developing rat prefrontal cortex and striatum. Developmental Brain Research 63: 229-235 (1992).
Wyrick, S.D., Booth, R.G., Myers, A.M., Kula, N.S., and Baldessarini, R.J. Synthesis of [N-C3H3]-racemic-trans-1-phenyl-3-dimethylamino-6-chloro-7-hydroxy-1,2,3,4-tetrahydronaphthalene (PAT-6). Journal of Labeled Compounds and Radiopharmaceuticals 31:871-874 (1992).
Baldessarini, R.J., Booth, R.G., Campbell, A., and Neumeyer, J.L. S(+)-Aporphines as potential limbic-selective antipsychotic agents. Schizophrenia Research 4: 311-312 (1991).
Booth, R.G., Baldessarini, R.J, and Campbell, A. Inhibition of dopamine synthesis in rat striatal minces: Evidence of autoreceptor supersensitivity to S(+) but not to R(–)-N-n-propylnorapomorphine after repeated pretreatment with fluphenazine. Biochemical Pharmacology 41: 2040-2043 (1991).
Booth, R.G. and Baldessarini, R.J. (+)-Benzomorphan sigma ligands stimulate dopamine synthesis in rat corpus striatum tissue. Brain Research 557: 349-352 (1991).
Booth, R.G., Baldessarini, R. J., Kula, N.S., Zong, R., Gao, Y., and Neumeyer, J.L. Presynaptic inhibition of dopamine synthesis in rat striatal tissue by enantiomeric mono- and dihydroxyaporphines. Molecular Pharmacology 38: 92-101 (1990).
Rollema, H., Booth, R.G., Caldera, P., Johnson, E.A., Lampen, P., Youngster, S.K., Trevor, A.J., Naiman, N., and Castagnoli, N. In vivo intracerebral microdialysis studies in rats of MPP+ analogs and related charged species. Journal of Medicinal Chemistry 33: 2221-2230 (1990).
Booth, R.G., and Baldessarini, R.J. Adenosine A2 stimulation of tyrosine hydroxylase activity in rat striatal minces is reversed by dopamine D2 autoreceptor activation. European Journal of Pharmacology 185: 217-221 (1990).
Booth, R.G., Baldessarini, R.J., Kula, N., and Neumeyer, J.L. Stereochemical effects of mono- and dihydroxyaporphines on presynaptic inhibition of tyrosine hydroxylase in vitro. Annals of New York Academy of Science 604: 592-595 (1990).
Booth, R.G., Trevor, A.J., Singer, T.P., and Castagnoli, N. Studies on semi-rigid tricyclic analogs of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Journal of Medicinal Chemistry 32: 473-477 (1989).
Booth, R.G., Castagnoli, N., and Rollema, H. Intracerebral microdialysis neurotoxicity studies of quinoline and isoquinoline derivatives related to MPTP/MPP+. Neuroscience Letters 100: 306-312 (1989).
Johnson, E.A., Wu, E.Y., Rollema, H., Booth, R.G., Trevor, A.J., and Castagnoli, N. MPP+ Analogs: In vivo neurotoxicity and inhibition of striatal synaptosomal dopamine uptake. European Journal of Pharmacology 166: 65-74 (1989).
Booth, R.G., Rollema, H., and Castagnoli, N. In vivo dopaminergic neurotoxicity of the 2-b-methyl-carbolinium ion, a potential endogenous MPP+ analog. European Journal of Pharmacology 153: 131-134 (1988).
Sirawaraporn, W., Sertsrivanich, R., Booth, R.G., Hansch, C., Neal, R.A., and Santi, D.V. Inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines. Molecular Biochemical Parasitology 31: 79-86 (1988).
Castagnoli, N., Trevor, A.J., Singer, T.P., Sparatore, A., Leung, L., Shinka, T., Wu., E.Y., and Booth, R.G. Metabolic studies on the nigrostriatal toxin MPTP. In Progress in Catecholamine Research, Alan R. Liss, Inc., New York, 93-100 (1988).
Booth, R.G., Selassie, C.D., Hansch, C., and Santi, D.V. Quantitative structure-activity relationship of triazine-antifolate inhibition of Leishmania dihydrofolate reductase and cell growth. Journal of Medicinal Chemistry 30: 1218-1224 (1987).
Ramsay, R.R., McKeown, K.A., Johnson, E.A., Booth, R.G., and Singer, T.P. Inhibition of NADH oxidation by pyridine derivatives. Biochemical and Biophysical Research Communications 146: 53-60 (1987).
