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

[enquirewithin]

Yes, David Nichols is one of the leading figures in research (real research!) into psychedelics, but he, unlike his friend Shulgin, has chosen to remain within the establishment. That's why he can't test any materials on humans.

He's behind the Hefter Institute.

[nanobrain]

^hence the 2 opposing? camps - rodents vs primates with the latter camp arguing that we have yet to develop the technology to accurately capture and adequately translate the nonphysical aspects of the psychedelic experience in the rat.

that said, he does have a rather few clever cookie grad / postgrad students with labs that are, by some accounts, not hermetically sealed. ;-)

[enquirewithin]

Experiments with slices of rat brains don't seem that interesting, but the 'other camp' do seem to get hold of these materials sooner or later. Not to mention underground chemists reading the journals and producing substances.

[Felonious Skunk]

People might be surprised that much of Nichols' research is funded by NIDA.

[Expat98]

Originally Posted by nanobrain

that said, he does have a rather few clever cookie grad / postgrad students with labs that are, by some accounts, not hermetically sealed. ;-)

Originally Posted by enquirewithin

Experiments with slices of rat brains don't seem that interesting, but the 'other camp' do seem to get hold of these materials sooner or later.

Some of the substances in PIHKAL were first synthesized in David Nichols' lab.

[enquirewithin]

^I'm not sure but I think Nichols is one of the 'characters' in PIHKAL.

Apart from, the 'flys', Nichols has worked on MDMA-related compounds too, including MBDB and the so-called "Flatliners" (4-MTA (p-methylthioamphetamine).

He agrees that Shulgin's testing is the only real way to find out about psychedelics but values his job at Purdue.

[radiometer]

Originally Posted by enquirewithin

^I'm not sure but I think Nichols is on of the 'characters' in PIHKAL.

I thought that was pretty obvious, though I've forgotten the name used.

[Panthers007]

Originally Posted by enquirewithin

^
He agrees that Shulgin's testing is the only real way to find out about psychedelics but values his job at Purdue.

Perdue? He must be chicken...

I'll go and hide now....

[enquirewithin]

Am I missing something here?

[trptamene]

lol perdue/purdue

[chaos69]

his lab does some pretty cool research. one of his new papers (he seems to pump them out every week) "'Hybrid' benzofuran-benzopyran congeners as rigid analogs of hallucinogenic phenethylamines. (2008)" was pretty interesting i thought. plus all that n-benzyl stuff is really cool.

Reputation Comments on this post:

Reading Good.

[enquirewithin]

[top]'Hybrid' benzofuran-benzopyran congeners as rigid analogs of hallucinogenic phenethylamines.

Schultz DM, Prescher JA, Kidd S, Marona-Lewicka D, Nichols DE, Monte A.
Department of Chemistry, University of Wisconsin-La Crosse, 1725 State Street, La Crosse, WI 54601, USA.
Phenylalkylamines that possess conformationally rigidified furanyl moieties in place of alkoxy arene ring substituents have been shown previously to possess the highest affinities and agonist functional potencies at the serotonin 5-HT(2A) receptor among this chemical class. Further, affinity declines when both furanyl rings are expanded to the larger dipyranyl ring system. The present paper reports the synthesis and pharmacological evaluation of a series of 'hybrid' benzofuranyl-benzopyranyl phenylalkylamines to probe further the sizes of the binding pockets within the serotonin 5-HT(2A) agonist binding site. Thus, 4(a-b), 5(a-b), and 6 were prepared as homologs of the parent compound, 8-bromo-1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminopropane 2, and their affinity, functional potency, and intrinsic activity were assessed using cells stably expressing the rat 5-HT(2A) receptor. The behavioral pharmacology of these new analogs was also evaluated in the two-lever drug discrimination paradigm. Although all of the hybrid isomers had similar, nanomolar range receptor affinities, those with the smaller furanyl ring at the arene 2-position (4a-b) displayed a 4- to 15-fold greater functional potency than those with the larger pyranyl ring at that position (5a-b). When the furan ring of the more potent agonist 4b was aromatized to give 6, a receptor affinity similar to the parent difuranyl compound 2 was attained, along with a functional potency equivalent to 2, 4a, and 4b. 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).

http://www.ncbi.nlm.nih.gov/pubmed/18467103

I am not really sure what that means!

[top]Substituted naphthofurans as hallucinogenic phenethylamine-ergoline hybrid molecules with unexpected muscarinic antagonist activity.

Monte AP, Marona-Lewicka D, Lewis MM, Mailman RB, Wainscott DB, Nelson DL, Nichols DE.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
A series of substituted racemic naphthofurans were synthesized as "hybrid" molecules of the two major prototypical hallucinogenic drug classes, the phenethylamines and the tryptamines/ergolines. Although it was hypothesized that these new agents might possess high affinity for the serotonin 5-HT2A/2C receptor subtypes, unexpected affinity for muscarinic receptors was observed. The compounds initially synthesized for this study were (+/-)-anti- and syn-4-amino-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1,8-bc]furan (4a,b), respectively, and their 8-bromo derivatives 4c,d, respectively. The brominated primary amines 4c,d were assayed initially for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0. 08 mg/kg). Also, 4c,d were evaluated for their ability to compete against agonist and antagonist radioligands at cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. After the syn diastereomers were found to have the highest activity in these preliminary assays, the N-alkylated analogues syn-N,N-dimethyl-4-amino-6-methoxy-2a,3,4, 5-tetrahydro-2H-naphtho[1,8-bc]furan (4e) and syn-N, N-dipropyl-4-amino-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1, 8-bc]furan (4f) were prepared and assayed for their affinities at [3H]ketanserin-labeled 5-HT2A and [3H]-8-OH-DPAT-labeled 5-HT1A sites. All of the molecules tested had relatively low affinity for serotonin receptors, yet a preliminary screen indicated that compound 4d had affinity for muscarinic receptors. Thus, 4b,d,e were evaluated for their affinity at muscarinic M1-M5 receptors and also assessed for their functional characteristics at the M1 and M2 isoforms. Compound 4d had affinities of 12-33 nM at all of the muscarinic sites, with 4b,e having much lower affinity. All three compounds fully antagonized the effects of carbachol at the M1 receptor, while only 4d completely antagonized carbachol at the M2 receptor. The fact that the naphthofurans lack LSD-like activity suggests that they do not bind to the serotonin receptor in a way such that the tricyclic naphthofuran nucleus is bioisosteric with, and directly superimposable upon, the A, B, and C rings of LSD. This also implies, therefore, that the hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation for these two chemical classes, contrary to previous hypotheses.

http://www.ncbi.nlm.nih.gov/pubmed/9622555?