David Nichols

Academic, Scientist

Dr. David E. Nichols is Professor Emeritus of Pharmacology at Purdue University and an Adjunct Professor at the University of North Carolina at Chapel Hill. He is also Chairman of the Board and a Co-Founder of the Heffter Research Institute. In addition, he held the position of Robert C. and Charlotte P. Anderson Distinguished Chair in Pharmacology at Purdue University for almost 38 years. Dr. Nichols earned his Bachelor’s Degree in Chemistry from the University of Cincinnati in 1969 and his Ph.D. in Medicinal Chemistry from the University of Iowa in 1973. Dr. Nichols also serves on the Scientific Advisory Board for the Beckley Foundation.

In 1986, Dr. Nichols wrote a highly-cited paper published in Pharmacology Biochemistry and Behavior in which he laid out the relationship between the molecular structure of compounds and their hallucinogenic activity.1 In this paper, he proposed a new class of hallucinogens called empathogens which he later renamed entactogens.

Dr. Nichols’ current research focuses on systems and receptors in the brain that use the neurotransmitters dopamine and serotonin.2-9 In 2004, he was invited to write a review paper for Pharmacology & Therapeutics on hallucinogens which has become a cornerstone publication with over 1,000 citations by other researchers.10  In 2013, Dr. Nichols wrote an article with Dr. David Nutt of Imperial College London and Leslie King on the impact of drug laws on scientific research which was published in Nature Reviews Neuroscience.11

Dr. Nichols lab also has a continuing interest in the serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors as likely targets for hallucinogenic/psychedelic substances and atypical antipsychotic drugs, and the possible roles that these receptor systems may play in normal cognitive function. These projects are comprised of systematic structural modification, coupled with pharmacological assay, with a view toward identifying structural determinants of the ligand binding domain in these receptors.

One theme of Dr. Nichol’s research has been to identify how molecules from different chemical classes can all be accommodated within the same receptor binding site. More recently he has been studying the second messenger systems that are coupled to the 5-HT2A receptor and investigating their relative importance in the actions of hallucinogenic drugs. He has also developed a computer-based homology model of several G protein-coupled receptors and are attempting to understand the functional elements within the receptor that are key to agonist activation.

    References
  1. Nichols DE. Studies of the relationship between molecular structure and hallucinogenic activity. Pharmacology Biochemistry and Behavior. 1986;24(2):335-340. doi:10.1016/0091-3057(86)90362-X
  2. Grubbs RA, Lewis MM, Owens-Vance C, et al. 8, 9-Dihydroxy-1, 2, 3, 11b-tetrahydrochromeno [4, 3, 2,-de] isoquinoline (dinoxyline), a high affinity and potent agonist at all dopamine receptor isoforms. Bioorganic & medicinal chemistry. 2004;12(6):1403-1412. doi:10.1016/j.bmc.2004.01.008
  3. Marona-Lewicka D, Thisted RA, Nichols DE. Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis. Psychopharmacology. 2005;180(3):427-435. doi:10.1007/s00213-005-2183-9
  4. Parrish JC, Braden MR, Gundy E, Nichols DE. Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT2A receptor agonists. Journal of Neurochemistry. 2005;95(6):1575-1584. doi:10.1111/j.1471-4159.2005.03477.x
  5. McLean TH, Chambers JJ, Parrish JC, et al. C-(4, 5, 6-trimethoxyindan-1-yl) methanamine: a mescaline analogue designed using a homology model of the 5-HT2A receptor. Journal of medicinal chemistry. 2006;49(14):4269-4274. doi:10.1021/jm060272y
  6. McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE. 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. Journal of medicinal chemistry. 2006;49(19):5794-5803. doi:10.1021/jm060656o
  7. Cueva JP, Giorgioni G, Grubbs RA, Chemel BR, Watts VJ, Nichols DE. trans-2, 3-Dihydroxy-6a, 7, 8, 12b-tetrahydro-6 H-chromeno [3, 4-c] isoquinoline: Synthesis, Resolution, and Preliminary Pharmacological Characterization of a New Dopamine D1 Receptor Full Agonist. Journal of medicinal chemistry. 2006;49(23):6848-6857. doi:10.1021/jm0604979
  8. Parrish JC, Nichols DE. Serotonin 5‐HT2A receptor activation induces 2‐arachidonoylglycerol release through a phospholipase c‐dependent mechanism. Journal of neurochemistry. 2006;99(4):1164-1175. doi:10.1111/j.1471-4159.2006.04173.x
  9. Braden MR, Parrish JC, Naylor JC, Nichols DE. Molecular interaction of serotonin 5 HT2A receptor residues Phe339 (6.51) and Phe340 (6.52) with super-potent N-benzyl phenethylamine agonists. Molecular Pharmacology. 2006. doi:10.1124/mol.106.028720
  10. Nichols DE. Hallucinogens. Pharmacology & Therapeutics. 2004;101(2):131-181. doi:10.1016/j.pharmthera.2003.11.002
  11. Nutt DJ, King LA, Nichols DE. Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nature Reviews Neuroscience. 2013;14(8):577-585. doi:10.1038/nrn3530