The objective of this work is to characterize further the functional topography and stereochemical requirements of the receptor types involved in the action of various hallucinogenic drugs. It is proposed to do this by the synthesis of a variety of novel analogs, including N(6)-alkyl-nor-LSD derivatives, certain enantiomeric analogs of substituted phenylisopropylamine and phenethylamine type hallucinogens, and several novel potential receptor alkylating agents. The latter types are exemplified by the proposed synthesis and evaluation of N(6)-(2-chloroethyl)-nor-LSD and several tertiary amino typtamine derivatives where one of the amine substituents is a beta-chloroethyl group. These compounds are all capable of generating a reactive aziridinium species at the receptor and alkylating nucleophiles that may be present, thus covalently labeling the receptor. Compounds will be tested for LSD-like biological activity using the two-lever drug discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). All compounds will be characterized in a radioligand receptor binding assay for affinity at 5-HT1, 5-HT2, D-1, and D-2 receptors. In addition, superfused and electrically-stimulated superfused slices of rat brain caudate nucleus, hippocampus and frontal cortex will be used to study release of 3H-labeled serotonin, dopamine, and norepinephrine, both in response to drug, and as affected by drug when electrical stimulation is applied. This may allow study both of presynaptic and postsynaptic action. Use of the potential alkylating agents should allow the identification of the receptor types that have been covalently labeled. Using this combination of enantiomeric probes, covalent labels, and biological assays, it should be possible to define further sites of action of LSD and other types of hallucinogens.

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National Institute on Drug Abuse (NIDA)
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Purdue University
Schools of Pharmacy
West Lafayette
United States
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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

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