1985 — 2010 |
Nichols, David E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Development of Potentially Selective Dopamine Agonists @ Purdue University West Lafayette
DESCRIPTION (provided by applicant): This application requests continued support of our drug design efforts aimed both at novel ligands that are dopamine receptor (DAR) isoform-selective agonists, and that can be used as tools to probe the structure and function of this subfamily of GPCRs. Although we are one of the few academic laboratories in the world actively pursuing these lines of research, this project has had a long and successful history in the design and synthesis of dopamine D1/D5 agonists, and their use in understanding DAR function. The design and synthesis efforts supported by this work occur in the context of an independently funded long-term collaboration that provides important pharmacological and computational input. One direction to be pursued is synthesis and characterization of new molecules that will permit the development of a body of data that would lead to the design of agonists selective for the D5, the D1, or both isoforms. These are classes of drugs that do not currently exist, but for which there would be exquisite research and even clinical utility. Full efficacy dopamine D1/D5 agonists are starting to be recognized for their potential as the most effective therapeutic agents for the treatment of mid- and late stage Parkinson's disease, and there is now good evidence that such agonists may also be useful in treating cognitive deficits induced by certain neuroleptics, improving memory, in reversing the negative symptoms of schizophrenia, etc. The approach to be employed is driven by medicinal chemistry and proposes the synthesis of structural modifications that focus on the B-phenyl-B-dopamine pharmacophore that we have identified and used as a template with outstanding success. We have produced three structurally diverse dopamine agonists from this template, and all of them have shown remarkable efficacy vs MPTP-parkinsonism in nonhuman primates. This work provides a foundation for molecular exploitation that will lead to additional important compounds. These will define structure-activity relationships that will help to define the nature of the binding domains necessary to activate the target dopamine receptors. We shall also follow-up on substantial improvements in pharmacokinetic properties we have made without sacrificing desired pharmacodynamic characteristics. 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.
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1985 — 2008 |
Nichols, David E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Stereochemical Aspects of Hallucinogenesis @ Purdue University West Lafayette
DESCRIPTION (from applicant's abstract): The major aims of this proposal are all focused on the serotonin 5-HT2A receptor, which is now being seen as a critical site for normal cognitive function and as a target for a typical antipsychotic agents. In the first aim, the PI will study how the oxygen substitution patterns in phenethylamine type 5-HT2A agonists affect orientation of the oxygen atom unshared electrons, which are clearly determinants of ligand recognition and activation. This information is critical to developing a 3D pharmacophore that can encompass all of the phenethylamine agonists possessing different substitution patterns. This aim will be accomplished by the synthesis of a variety of rigid analogues wherein the oxygen function is tethered into a ring of varying size, that forces the oxygen atom to adopt a particular conformation. Target molecules will be evaluated for both affinity and efficacy at the cloned rat 5-HT2a receptor, and will also be assessed for specificity at the cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors through a collaborative effort. The second aim is directed toward a study of the hypothesis that the late phases of LSD intoxication may resemble certain aspects of paranoid psychosis, a suggestion made by D.X. Freedman. In particular, we hypothesize that the initial 5-HT2A stimulatory effect of LSD sensitizes brain dopamine pathways to the effect of a potent dopaminergic metabolite, 13-hydroxy-LSD, which may accumulate during the action of LSD, and that this metabolite plays a key role in the psychopharmacology of the second temporal phase of LSD intoxication. These studies would have relevance to understanding possible roles of the 5-HT2A receptor in psychosis and schizophrenia. Major effort in this aim will be directed toward the synthesis and characterization of 13-hydroxy ergolines, using new approaches for construction of the ergoline nucleus. Drug discrimination studies will be employed to examine the nature of the LSD cue, as a function of time after administration, with a particular emphasis on the possibility that dopaminergic effects will predominate in the interoceptive cue at later times after LSD administration. The third aim is directed toward the synthesis of new, extremely potent (subnanomolar), agonist ligand for the 5-HT2 family of receptors. The initial target will be a molecule that can be tritiated to provide a radioligand with very high affinity and relatively high specific activity. 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.
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1988 — 1990 |
Nichols, David E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Structure-Activity Studies of Mdma-Like Substances @ Purdue University West Lafayette
Recently, 3, 4-methylenedioxymethamphetamine (MDMA) became popular as a recreational substance of abuse and was subsequently placed into Schedule I of the Controlled Substances Act. Although MDMA is structurally related to the hallucinogenic amphetamines, it may possess novel psychoactive properties. In view of MDMA's recreational popularity, and its potentially novel pharmacological properties, it is important to understand how MDMA works. This proposal describes a comprehensive program to: 1. study the behavioral properties of MDMA and related compounds, in the drug discrimination paradigm in rats, and to compare MDMA with other, known psychoactive phenethylamine derivatives in this model, 2. to study the biochemical pharmacology of MDMA and related compounds for an effect on monoamines neurotransmitter function in rat brain synaptosomes, with particular emphasis on comparison of neurotransmitter uptake and release mechanisms, 3. to measure the binding affinity of 3H-labeled enantiomers of MDMA and its alpha-ethyl congener MBDB, and to generate displacement curves with a variety of neurochemicals to fully characterize MDMA binding sites, and 4. to synthesize a series of structurally-related compounds, and to assay their pharmacology. These studies will provide further elucidation of the mechanism of action of MDMA and related compounds, and will define the structure-activity relationships wherein compounds with an MDMA-like effect are likely to be found.
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1991 — 1993 |
Nichols, David E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Structure Activity Studies of Mdma-Like Substances @ Purdue University West Lafayette
This proposal presents, for synthesis and pharmacological evaluation, series of 2-aminoindans, enantiomers of alpha-ethyltryptamines, certain benzofuran congeners, and [125I]-labeled analogs of the novel psychoactive agent 3,4-methylenedioxymethamphetamine (MDMA). Structures are based upon our previous findings that certain alpha- ethylphenethylamines and rigid analogs of MDMA possess animal behavioral pharmacology similar to MDMA, but have attenuated dopaminergic properties and decreased serotonin neurotoxicity. The target structures will serve as pharmacological tools for several purposes: to aid in elucidation of the mechanism of action of MDMA, to further refine the structure-activity relationships of MDMA-like drugs, to study certain components of the neurotoxic effects of MDMA-like agents, and to be used to help elucidate the role of serotonin in certain behavioral states. In particular, following synthesis, new compounds will be tested for MDMA-like behavioral pharmacology using the two-lever drug discrimination paradigm, in rats trained to discriminate saline form the alpha-ethyl homolog of MDMA,(+)-MBDB. Compounds which fully substitute will then be examined for ability to inhibit uptake or effect release of serotonin (5-HT), dopamine, or norepinephrine from rat brain synaptosomes. Compounds showing high selectivity for 5-HT will be further evaluated for acute in vivo effects on brain monoamine and metabolite levels. After multiple dosing with these compounds and sacrifice at 1-week, examination of brain monoamines, their metabolites, and radioligand binding parameters using the 5-HT uptake inhibitor [3H]- paroxetine, will be used as indicators of serotonin neurotoxic potential. Compounds will be evaluated for reinforcing properties using the conditioned place preference paradigm. Compounds which do not induce place preference will be tested for their ability to antagonize (+)-amphetamine-induced place conditioning, as potential antagonist of the reinforcing properties of psychostimulants. Formal collaborative arrangements have been developed with five other laboratories to study further new compounds for locomotor activating effects in rats, ability to increase extracellular dopamine measured by in vivo microdialysis, and the radiosynthesis and use of certain neurotoxic and nonneurotoxic [125I]-ligands to visualize 5-HT neurons in rat brain. Also through a collaborative arrangement, compounds that block amphetamine-induced place preference will be tested for an ability to antagonize the reinforcing effects of cocaine in rats that intravenously self- administer cocaine.
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1995 — 1998 |
Nichols, David E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Novel Serotonin Releasing Agents @ Purdue University West Lafayette
This project outlines studies designed to lead to the development of chemical molecules which have the ability specifically to release endogenous serotonin from brain serotonin neurons. The target compounds will not produce long-term deficits in central serotonin markers, as is typical of other such agents such as parachloroamphetamine or fenfluramine. This project has immediate application, as the drugs which are developed will be useful as pharmacological tools to study the role of brain serotonin systems in a variety of behaviors. These molecules should have significance to the study of serotonin systems comparable to that of amphetamine for studying dopaminergic systems. The long range significance of this work will lie in a better understanding of the role serotonin plays in emotion and behavior. In addition, serotonin-releasing agents may prove to have utility in the treatment of conditions such as depression and anxiety disorders which are now effectively treated with serotonin uptake inhibitors. This proposal targets several types of chemical structures, including para-alkylthioamphetamine derivatives, 5- alkylthio-2-aminoindans, ring-methylated 3,4-methylenedioxyamphetamine derivatives, and 5-trifluoromethyl-2-aminoindan and its N-ethyl derivative, the latter which are rigid analogues of fenfluramine and norfenfluramine. Following synthesis, new compounds will be screened in a battery of assays, initially including ability to inhibit monoamine accumulation into rat brain synaptosomes and to induce the overflow of transmitter from prelabeled superfused synaptosomes. In addition, tests for cross-substitution in the two-lever drug discrimination paradigm will assess whether the compounds are more similar in vivo to serotonin releasing agents, hallucinogens, or psychostimulants. Acute and long-term effects on brain monoamines will be assessed using HPLC-EC, with a particular emphasis on acute and long-term effects on serotonin neuron markers as an indication of potential serotonergic neurotoxicity of new compounds. This will provide data to continue our testing of the hypothesis that substituted amphetamines must release both serotonin and dopamine to induce long-term serotonergic deficits. Compounds will be evaluated for reinforcing effects using conditioned place preference, to assess the validity of the hypothesis that only compounds with dopaminergic activity will induce place preference. In vivo microdialysis will be used to measure changes in extracellular dopamine in the rat nucleus accumbens to test further the hypothesis that increased accumbens dopamine levels are correlated with ability to induce place preference.
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