This is a highly interdisciplinary proposal to continue our efforts to understand the structure-activity relationships of hallucinogens: drugs that are agonists at the serotonin 5-HT2A receptor. It involves computer-assisted ligand design and receptor docking studies, in vitro and in vivo pharmacology, and molecular biology methods. More specifically, it builds on a recent homology model of the serotonin 5-HT2A receptor that we have developed in our laboratory, and proposes a number of specific mutations within the putative ligand binding domain. These mutations will be combined with pharmacological assessment of small agonist ligands to be synthesized or already in our extensive library, in order to examine functional complementation of binding and activation, the most powerful technique presently available for identification of direct ligand contacts within a receptor. Conformationally-constrained phenethylamine ligands also have been designed specifically to probe the relationship between the conformation of the aminoethyl side chain and the aromatic ring in agonist-receptor interactions. In addition, a strategy is also proposed to develop an agonist ligand that should have high affinity for the 5-HT2A receptor, but which should possess low affinity for the 5-HT2c receptor. A short series of derivatives of a novel template we have recently developed with high affinity for the serotonin 5-HT1A receptor is also proposed and, along with known agonist ligands for this receptor, a homology model for the 5-HT1A receptor will be refined using methods similar to those we used for the 5-HT2A receptor. Finally, we shall continue our investigations into the nature of the biphasic action of the potent hallucinogenic agent LSD, where we have discovered that the effects of LSD in rats are mediated initially by activation of 5-HT2A receptors, but in a later temporal phase dopamine systems appear to be activated. In addition, we shall study the underlying basis for the behavioral sensitization that occurs following long-term LSD administration to rats. These studies will involve examination of a number of antipsychotic drugs to determine whether they can attenuate or block LSD-induced behavioral sensitization in rats either acutely, or following continuous administration. We also propose the synthesis of a 13-hydroxyergoline as a potential dopaminergic compound, to assess the potential dopaminergic activity of the 13-hydroxy metabolite of LSD. These studies may lead to a rat model of schizophrenia that could be very useful in developing and understanding new types of antipsychotic agents.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Hillery, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Purdue University
Schools of Pharmacy
West Lafayette
United States
Zip Code
Nichols, David E (2016) Psychedelics. Pharmacol Rev 68:264-355
Martin, David A; Marona-Lewicka, Danuta; Nichols, David E et al. (2014) Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. Neuropharmacology 83:1-8
Juncosa Jr, Jose I; Hansen, Martin; Bonner, Lisa A et al. (2013) Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands. ACS Chem Neurosci 4:96-109
Bekkam, Markondaiah; Mo, Huaping; Nichols, David E (2012) A reported ""new synthesis of lysergic acid"" yields only the derailment product: methyl 5-methoxy-4,5-dihydroindolo[4,3-f,g]quinoline-9-carboxylate. Org Lett 14:296-8
Marona-Lewicka, Danuta; Nichols, Charles D; Nichols, David E (2011) An animal model of schizophrenia based on chronic LSD administration: old idea, new results. Neuropharmacology 61:503-12
McCorvy, John D; Harland, Aubrie A; Maglathlin, Rebecca et al. (2011) A 5-HT(2C) receptor antagonist potentiates a low dose amphetamine-induced conditioned place preference. Neurosci Lett 505:10-3
Marona-Lewicka, Danuta; Nichols, David E (2009) WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D(4) receptor activation. Behav Pharmacol 20:114-8
Trachsel, Daniel; Nichols, David E; Kidd, Stephanie et al. (2009) 4-aryl-substituted 2,5-dimethoxyphenethylamines: synthesis and serotonin 5-HT(2A) receptor affinities. Chem Biodivers 6:692-704
Nichols, David E; Frescas, Stewart P; Chemel, Benjamin R et al. (2008) High specific activity tritium-labeled N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (INBMeO): a high-affinity 5-HT2A receptor-selective agonist radioligand. Bioorg Med Chem 16:6116-23
Schultz, Danielle M; Prescher, Jennifer A; Kidd, Stephanie et al. (2008) 'Hybrid'benzofuran-benzopyran congeners as rigid analogs of hallucinogenic phenethylamines. Bioorg Med Chem 16:6242-51

Showing the most recent 10 out of 67 publications