Research Topics
| David NicholsSummaryAffiliation: Purdue University Country: USA Publications
Research Grants
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Detail Information
Publications
Serotonin 5-HT(2A) receptor activation induces 2-arachidonoylglycerol release through a phospholipase c-dependent mechanismJason C Parrish
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 4790, USA
J Neurochem 99:1164-75. 2006....- Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD)David E Nichols
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA
J Med Chem 45:4344-9. 2002..The incorporation of isomeric dialkylazetidines into other biologically active molecules may be a useful strategy to model the active conformations of dialkylamines and dialkylamides... 
High specific activity tritium-labeled N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (INBMeO): a high-affinity 5-HT2A receptor-selective agonist radioligandDavid E Nichols
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, 1333 Robert E Heine Pharmacy Building, West Lafayette, IN 47907, USA
Bioorg Med Chem 16:6116-23. 2008..The new radioligand was suitable for labeling human 5-HT(2A) receptors in two heterologous cell lines and had about 20-fold higher affinity than [(3)H]ketanserin...- Serotonin receptorsDavid E Nichols
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47906-2091, USA
Chem Rev 108:1614-41. 2008 - 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonistsThomas H McLean
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907-1333, USA
J Med Chem 49:5794-803. 2006..If hallucinogenic effects are correlated with arachidonic acid production, such functionally selective 5-HT(2A) receptor agonists may lack the intoxicating properties of hallucinogens such as LSD... - Synthesis and pharmacological characterization of a series of geometrically constrained 5-HT(2A/2C) receptor ligandsJames J Chambers
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-1333, USA
J Med Chem 46:3526-35. 2003..Thus, although conformational constraint has led to high-affinity 5-HT(2A) ligands with partial agonist activity, all of the spatial and steric properties of the ligand necessary for full receptor activation have not yet been identified... - C-(4,5,6-trimethoxyindan-1-yl)methanamine: a mescaline analogue designed using a homology model of the 5-HT2A receptorThomas H McLean
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907 1333, USA
J Med Chem 49:4269-74. 2006..Resolution of this analogue into its enantiomers corroborated the docking experiments, showing the R-(+) isomer to have higher affinity and potency and to have efficacy similar to that of mescaline at the 5-HT(2A) receptor... - HallucinogensDavid E Nichols
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907 2091, USA
Pharmacol Ther 101:131-81. 2004..In addition, it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders... - Translocation of the 5-alkoxy substituent of 2,5-dialkoxyarylalkylamines to the 6-position: effects on 5-HT(2A/2C) receptor affinityJames J Chambers
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-1333, USA
Bioorg Med Chem Lett 12:1997-9. 2002.... - trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonistJuan Pablo Cueva
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA
J Med Chem 49:6848-57. 2006..The binding and functional properties of this compound illustrate again the utility of constructing dopamine D1 agonist ligands around the beta-phenyldopamine pharmacophore template... 
Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOIDanuta Marona-Lewicka
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences RHPH, Purdue University, 575 Stadium Mall Dr, West Lafayette, IN 47907 2091, USA
Psychopharmacology (Berl) 203:265-77. 2009..Lysergic acid diethylamide (LSD) differs from other types of hallucinogens in that it possesses direct dopaminergic effects. The exact nature of this component has not been elucidated...- Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reservesDeborah M Kurrasch-Orbaugh
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacological Sciences, Purdue University, West Lafayette, Indiana 47907, USA
J Pharmacol Exp Ther 304:229-37. 2003..From these data we conclude that structurally distinct ligands can differentially regulate 5-HT 2A receptor signal transduction... - Further evidence that the delayed temporal dopaminergic effects of LSD are mediated by a mechanism different than the first temporal phase of actionDanuta Marona Lewicka
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, RHPH, 575 Stadium Mall Dr Purdue University, West Lafayette, IN 47907 2091, United States
Pharmacol Biochem Behav 87:453-61. 2007..The results reported here support and extend our previous conclusion that the delayed temporal effects of LSD are mediated by activation of a dopaminergic system... - Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosisDanuta Marona-Lewicka
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, Heine Pharmacy Building, 575 Stadium Mall Dr, West Lafayette, IN 47907-2091, USA
Psychopharmacology (Berl) 180:427-35. 2005..A second temporal phase that involves dopaminergic pathways would be consistent with the widespread belief that excessive dopaminergic activity may be an underlying cause of paranoid psychosis... - Differential phospholipase C activation by phenylalkylamine serotonin 5-HT 2A receptor agonistsJason C Parrish
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907-2091, USA
J Neurochem 95:1575-84. 2005.... - A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinasesDeborah M Kurrasch-Orbaugh
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana, USA
J Neurochem 86:980-91. 2003.... - Distinct molecular recognition of psychostimulants by human and Drosophila serotonin transportersDavid L Roman
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-2091, USA
J Pharmacol Exp Ther 308:679-87. 2004..For the substituted amphetamines, key areas for interaction exist around the amine, an electrostatic component surrounding the 3-position on the aromatic ring, and a steric component surrounding the 4-position... - Synthesis and pharmacological evaluation of substituted naphth[1,2,3-de]isoquinolines (dinapsoline analogues) as D1 and D2 dopamine receptor ligandsAmjad M Qandil
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA
Bioorg Med Chem 11:1451-64. 2003..Moreover, as rigid ligands in which small substituents can cause significant changes in selectivity, they are important tools for deriving 'differential' SARs of the dopamine receptor isoforms... - Comparison of the enantiomers of (+/-)-doxanthrine, a high efficacy full dopamine D(1) receptor agonist, and a reversal of enantioselectivity at D(1) versus alpha(2C) adrenergic receptorsJulie A Przybyla
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
Eur Neuropsychopharmacol 19:138-46. 2009..These findings demonstrate a reversed stereoselectivity for the enantiomers of DOX at D(1) and alpha(2C) receptors and have implications for the therapeutic utility of doxanthrine... - WAY-100635 is a potent dopamine D4 receptor agonistBenjamin R Chemel
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091, USA
Psychopharmacology (Berl) 188:244-51. 2006.... - 1-Methylpyridinium-4-(4-phenylmethanethiosulfonate) iodide, MTS-MPP+, a novel scanning cysteine accessibility method (SCAM) reagent for monoamine transporter studiesAlejandra Gallardo-Godoy
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47906, USA
Bioorg Med Chem 15:305-11. 2007..Although it did not prove to be a substrate, as is MPP(+), it appears to label cysteine residues lining the permeation pore of the transporter more readily than currently available nonspecific SCAM reagents... - Structural analysis of the extracellular entrance to the serotonin transporter permeation pathwayMelissa I Torres-Altoro
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy and Pharmaceutical Sciences, West Lafayette, Indiana 47907 2091, USA
J Biol Chem 285:15369-79. 2010..Our studies suggest that substrate and ligand binding may induce conformational shifts in TMH I and/or VI, providing new opportunities to refine existing homology models of SERT and related monoamine transporters... - Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in ratsDanuta Marona-Lewicka
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA
Psychopharmacology (Berl) 164:93-107. 2002..CONCLUSION: We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT(1A) receptors... - A homology-based model of the human 5-HT2A receptor derived from an in silico activated G-protein coupled receptorJames J Chambers
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-1333, USA
J Comput Aided Mol Des 16:511-20. 2002..The ligand/receptor complexes that ensued were refined and the final binding orientations were observed to be compatible with much of the data acquired through both diversified ligand design and site directed mutagenesis... - The role of lipophilicity in determining binding affinity and functional activity for 5-HT2A receptor ligandsMatthew A Parker
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47906, USA
Bioorg Med Chem 16:4661-9. 2008..The results suggest a possible method for distinguishing agonists from antagonists in high-throughput screening when a direct assay for functional activity is either unavailable or impractical... - Comparative molecular field analysis using selectivity fields reveals residues in the third transmembrane helix of the serotonin transporter associated with substrate and antagonist recognitionCrystal C Walline
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
J Pharmacol Exp Ther 325:791-800. 2008..A SERT homology model developed from the Aquifex aeolicus leucine transporter structure provides a structural context for further interpreting the results of the TMH III mutations... - WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D(4) receptor activationDanuta Marona-Lewicka
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907 2091, USA
Behav Pharmacol 20:114-8. 2009..These results indicate that the discriminative stimulus effect produced by WAY 100635 is mediated by activation of dopamine D(4) receptors... - Facile synthesis of octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonistsLisa A Bonner
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States
Bioorg Med Chem 18:6763-70. 2010..Importantly, we demonstrate that the 7,8-dihydroxy-5-phenyl-substituted ligand is an extremely potent, high-affinity, full D1 dopamine receptor-selective agonist... - 8,9-dihydroxy-1,2,3,11b-tetrahydrochromeno[4,3,2,-de]isoquinoline (dinoxyline), a high affinity and potent agonist at all dopamine receptor isoformsRussell A Grubbs
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA
Bioorg Med Chem 12:1403-12. 2004..These rigid ligands also will be useful tools to determine specific residues of the receptor transmembrane domains that are critical for agonist ligand selectivity for the D(4) receptor... - Assessment of the roles of serines 5.43(239) and 5.46(242) for binding and potency of agonist ligands at the human serotonin 5-HT2A receptorMichael R Braden
Dept of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, 575 Stadium Mall Drive, Purdue University, West Lafayette, IN 47907 2091, USA
Mol Pharmacol 72:1200-9. 2007..50, a strong interaction with Ser5.43(239) may be more effective in straightening the kink in helix 5, a feature that is possibly common to all type A GPCRs that have polar residues at position 5.43... - Engineered zinc-binding sites confirm proximity and orientation of transmembrane helices I and III in the human serotonin transporterKellie J White
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy and Pharmaceutical Sciences, West Lafayette, Indiana 47907, USA
Protein Sci 15:2411-22. 2006..Homology modeling of the proposed Zn2+-binding sites using the coordinates of the Aquifex aeolicus leucine transporter structure provided a structural basis for interpreting the results and developing conclusions... - Substituted hexahydrobenzodipyrans as 5-HT2A/2C receptor probesMichael S Whiteside
Department of Chemistry, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA
Bioorg Med Chem 10:3301-6. 2002.... - 'Hybrid' benzofuran-benzopyran congeners as rigid analogs of hallucinogenic phenethylaminesDanielle M Schultz
Department of Chemistry, University of Wisconsin La Crosse, 1725 State Street, La Crosse, WI 54601, USA
Bioorg Med Chem 16:6242-51. 2008..In drug discrimination experiments using rats trained to discriminate LSD from saline, 4b was more than two times more potent than 5b, with the latter having a potency similar to the classic hallucinogenic amphetamine 1 (DOB)... - Sulfur-substituted alpha-alkyl phenethylamines as selective and reversible MAO-A inhibitors: biological activities, CoMFA analysis, and active site modelingAlejandra Gallardo-Godoy
Department of Chemistry, Faculty of Sciences, Universidad de Chile, Casilla 653, Santiago, Chile
J Med Chem 48:2407-19. 2005..On the basis of these results, structural determinants for selectivity of substituted amphetamines for MAO-A are discussed... - An antisense oligonucleotide targeted at MAO-B attenuates rat striatal serotonergic neurotoxicity induced by MDMAErin M Falk
The Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada 45810, USA
Pharmacol Biochem Behav 72:617-22. 2002..These results indicate that MAO-B plays an integral role in the development of MDMA-induced neurotoxicity while not affecting MDMA-induced hyperthermia or acute DA release... - Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclaseDavid M Mottola
Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7160, USA
J Pharmacol Exp Ther 301:1166-78. 2002.... - Synthesis and SAR exploration of dinapsoline analoguesSing Yuen Sit
Department of Neuroscience Drug Discovery Chemistry, Bristol Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492 7660, USA
Bioorg Med Chem 12:715-34. 2004..It was found that affinity for both D(1)and D(2) receptors was decreased by most substituents on the A, B', and C rings, whereas D ring substitutions preserved much of the dopamine receptor binding activity... - A demand for clarity regarding a case report on the ingestion of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) in an Ayahuasca preparationJ C Callaway
J Anal Toxicol 30:406-7; author reply 407. 2006 - Functional selectivity and classical concepts of quantitative pharmacologyJonathan D Urban
Curriculum in Toxicology, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7160, USA
J Pharmacol Exp Ther 320:1-13. 2007..It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts... - Functional selectivity of D2 receptor ligands in a Chinese hamster ovary hD2L cell line: evidence for induction of ligand-specific receptor statesElaine A Gay
Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA
Mol Pharmacol 66:97-105. 2004..We hypothesize that this functional selectivity may be a result of ligand induction of specific conformations of the D(2L) receptor that activate only selected signaling pathways... - Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonistsJessica P Ryman-Rasmussen
Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA
Mol Pharmacol 68:1039-48. 2005..These data are consistent with the hypothesis that functional selectivity reflects subtle ligand-induced conformational changes as opposed to simple agonist trafficking among discrete receptor active states... - 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated production of hydrogen peroxide in an in vitro model: the role of dopamine, the serotonin-reuptake transporter, and monoamine oxidase-BSandra L Hrometz
The Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810, USA
Neurosci Lett 367:56-9. 2004..These findings support the hypothesis that the deamination of DA by MAO-B within the serotonergic cell can lead to hydrogen peroxide formation and ultimately cell death... - Ambient temperature effects on 3,4-methylenedioxymethamphetamine-induced thermodysregulation and pharmacokinetics in male monkeysMatthew L Banks
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA
Drug Metab Dispos 35:1840-5. 2007..Overall, induction of hypothermia in a cool environment by MDMA may alter its disposition. These results could have implications for MDMA-induced serotonergic consequences... - Neurotoxicity of MDMA (ecstasy): beyond metabolismJon E Sprague
Trends Pharmacol Sci 26:59-60; author reply 60-1. 2005
Research Grants
- DEVELOPMENT OF POTENTIALLY SELECTIVE DOPAMINE AGONISTSDavid E Nichols; Fiscal Year: 2010..Our work will generate molecular probes that should help to increase our understanding of these pathways, and may also provide new therapies for disorders such as Parkinson's disease and schizophrenia. ..
- STEREOCHEMICAL ASPECTS OF HALLUCINOGENESISDavid Nichols; Fiscal Year: 2002..A fourth aim is directed toward further examination of the effect of ring-fluorination on receptor selectivity of tryptamines. In particular, these studies are directed toward the preparation of new 5-HT1A receptor selective agonists. ..
- DEVELOPMENT OF POTENTIALLY SELECTIVE DOPAMINE AGONISTSDavid Nichols; Fiscal Year: 2000....
- STEREOCHEMICAL ASPECTS OF HALLUCINOGENESISDavid Nichols; Fiscal Year: 2007..These studies may lead to a rat model of schizophrenia that could be very useful in developing and understanding new types of antipsychotic agents. ..
- DEVELOPMENT OF POTENTIALLY SELECTIVE DOPAMINE AGONISTSDavid Nichols; Fiscal Year: 2007..Our work will generate molecular probes that should help to increase our understanding of these pathways, and may also provide new therapies for disorders such as Parkinson's disease and schizophrenia. ..
- DEVELOPMENT OF POTENTIALLY SELECTIVE DOPAMINE AGONISTSDavid Nichols; Fiscal Year: 2005..The products of this work have a high likelihood of significant impact on basic studies of receptor function, and on the therapy of numerous CNS disorders. ..
- STEREOCHEMICAL ASPECTS OF HALLUCINOGENESISDavid Nichols; Fiscal Year: 1980..Also proposed is the development of an asymmetric synthesis for enantiomers of alpha-methyltryptamines...
- DEVELOPMENT OF POTENTIALLY SELECTIVE DOPAMINE AGONISTSDavid Nichols; Fiscal Year: 1993..These may encompass differing requirements for agonist versus antagonist binding, and may allow similarities and differences between the D1 and D2 receptors to be more clearly defined...
- DEVELOPMENT OF POTENTIALLY SELECTIVE DOPAMINE AGONISTSDavid Nichols; Fiscal Year: 1990..Structure-activity relationships will be developed for these classes, and attempts will be made to develop a three-dimensional topographical model of the dopamine D-1 receptor...
- STEREOCHEMICAL ASPECTS OF HALLUCINOGENESISDavid Nichols; Fiscal Year: 1993....
- STEREOCHEMICAL ASPECTS OF HALLUCINOGENESISDavid Nichols; Fiscal Year: 1991..Molecular mechanics procedures will be used to model the conformational mobility and preferred conformations in these series...