Other - Research of David E. Nichols

[trptamene]

I came across this and thought it would be of interest to some:

David E. Nichols is probably well known to most here for his work on bromodragonfly.

This is from his research site:

Originally Posted by David E. Nichols

Research: Medicinal and Bioorganic Chemistry
Molecular Pharmacology and Toxicology
The general thrust of the work in our laboratory could be characterized as the development of molecular probes to understand the role of brain monoamine neurotransmitters in normal behavior. Although molecular biology has made great strides in providing information about structural and functional aspects of the brain, those studies must be complemented through the use of specifically designed molecules that are directed toward particular biological targets. In an academic sense, such molecules are useful in gaining fundamental information about neuronal function. When one of them has high efficacy and low toxicity, however, it may become a drug candidate.
We have a particular focus on brain systems that utilize dopamine or serotonin as the neurotransmitter. In the former case, we are interested in molecular probes that have specificity for only one of the five general types of dopamine receptors (D1 - D5). Our efforts to date have led to several novel series of molecules that are full efficacy agonists at the dopamine D1 receptor subtype. One of these (named Dihydrexidine) showed remarkable efficacy in an animal model of late stage Parkinson's disease. A second-generation compound named dinapsoline has properties similar to dihydrexidine. Dinapsoline now has also shown dramatic efficacy in both rodent and primate models of Parkinson's disease. Recently we have developed yet a third series of related compounds based around a prototype named dinoxyline that is a sort of "universal" dopamine agonist. By appropriate structural modifications, these different templates have led to molecules with specificity for the D2 or D3 dopamine receptor isoforms.
We also have 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 this work has been to identify how molecules from different chemical classes can all be accommodated within the same receptor binding site. More recently we have 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. We have 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.
Representative Publications
D.E. Nichols. "Hallucinogens." Invited review for Pharmacology & Therapeutics, 101, 131-181 (2004).
R.A. Grubbs, M.M. Lewis, C. Owens-Vance, E. Arrington, A. Jassen, R.B. Mailman,and D.E. Nichols. "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," Bioorg. & Med. Chem., 12, 1403-1412 (2004).
D. Marona-Lewicka and D.E. Nichols. "Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 Receptor-mediated effects in the rat and implications for psychosis," Psychopharmacology, 180, 427-435 (2005).
J.C. Parrish, M.R. Braden, E. Gundy, and D.E. Nichols. "Differential phospholipase C activation by phenylalkylamine serotonin 5-HT2A receptor agonists," J. Neurochem., 95, 1575-1584, (2005).
T. McLean, J.J. Chambers, J.C. Parrish, M.R. Braden, D. Marona-Lewicka, D.M. Kurrasch-Orbaugh, and D.E. Nichols. "C-(4,5,6-trimethoxyindan-1-yl)-methanamine: a mescaline analogue designed using a homology model of the 5-HT2A receptor," J. Med. Chem., 49, 4269-4274 (2006).
B. Chemel, B.L. Roth, V.J. Watts, and D.E. Nichols. "The "selective" 5-HT1A antagonist WAY-100635 and its metabolite, WAY-100634, are potent dopamine D4 receptor agonists," Psychopharmacology, 188, 244-251 (2006).
T.H. McLean, J.C. Parrish, M.R. Braden, D. Marona-Lewicka, A. Gallardo-Godoy, and D.E. Nichols. "1-Aminomethylbenzocycloalkanes: conformationally-restricted hallucinogenic phen¬ethylamine analogues as functionally-selective 5 HT2A receptor agonists," J. Med. Chem., 49, 5794-5803 (2006).
J.P. Cueva, G. Giorgioni, R.A. Grubbs, B.R. Chemel, V.J. Watts, and D.E. Nichols. "Trans-2,3-dihydroxy-6a,78,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline; synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist," J. Med. Chem., 49, 6848-6857 (2006).
J.C. Parrish and D.E. Nichols. "Serotonin 5-HT2A receptor activation induces 2-arachi¬donoylglycerol (2-AG) release through a Phospholipase C-dependent mechanism," J. Neurochem., 99, 1164-1175 (2006).
M.R. Braden, J.C. Parrish, J.C. Naylor, and D.E. Nichols. "Molecular interaction of serotonin 5 HT2A receptor residues Phe339(6.51) and Phe340(6.52) with super-potent N-benzyl phenethylamine agonists," Mol. Pharmacol., 70, 1956-1964 (2006).

http://www.mcmp.purdue.edu/faculty/?uid=drdave

Originally Posted by Wiki

David E. Nichols (born December 23, 1944) is an American pharmacologist and medicinal chemist.

Presently the Robert C. and Charlotte P. Anderson Distinguished Chair in Pharmacology at Purdue University, Nichols has worked in the field of psychoactive drugs since 1969. While still a graduate student, he patented the method that is used to make the optical isomers of hallucinogenic amphetamines. His contributions include the synthesis and reporting of escaline and the coining of the term entactogen.

His work as a chemist is interesting in that he is still carrying out legitimate research on the chemistry of psychedelics. He has published appoximately 250 scientific reports and book chapters, all describing the relationship between the structure of a molecule and its biological effects (often referred to as a Structure-activity relationship, or SAR). Although his research mostly uses rats, a number of compounds included in Shulgin's PIHKAL were actually first synthesized in the Nichols' lab. His lab also first developed [125I]-(R)-DOI as a radioligand. Nichols is perhaps one of the few people in the last 20 years who has had interest in doing any legitimate research on the chemistry and pharmacology of LSD, and first reported that several LSD analogues, including ETH-LAD, PRO-LAD, and AL-LAD, were more potent than LSD itself. Their human effects are described in TiHKAL. He also improved the synthesis of psilocybin so that it would be accessible for several recent clinical studies.

He is the founding president of the Heffter Research Institute, named after German chemist and pharmacologist Arthur Heffter, who first discovered that mescaline was the active component in the peyote cactus. In 2004 he was named the Irwin H. Page Lecturer by the International Serotonin Club, and delivered an address in Portugal titled, "35 years studying psychedelics: what a long strange trip it's been." Among pharmacologists, he is considered to be one of the world's top experts on psychedelics.

Dr. Nichols' other professional activities include teaching medicinal chemistry and molecular pharmacology at Purdue University in West Lafayette, IN. He is one of the world leaders in research on dopamine, and is the principal chemist studying the importance of dopamine receptor D1 in the brain. He co-founded DarPharma, Inc. to commercialize his dopamine compounds; his compounds are now being studied in clinical trials for the treatment of Parkinson's disease and the cognitive and memory deficits of schizophrenia. He also teaches medical students at the Indiana University School of Medicine.

On Friday, September 28. 2007, the Purdue University Board of Trustees appointed Dr. Nichols to The Robert C. and Charlotte P. Anderson Distinguished Chair of Pharmacology.

http://en.wikipedia.org/wiki/David_E._Nichols