This proposal presents for synthesis and pharmacological evaluation: (1) a series of lysergic acid amides wherein the amide substituent is derived from a chiral amine, (2) a tricyclic ergoline analogue where the pyrrole ring of the ergoline has been replaced with a dihydrofuran ring and, (3) a benz[cd]indole with a pyrrolidine ring cis-fused across the 4-amino-C(3) positions. The latter two series will be resolved into their enantiomers. All compounds will be tested for substitution in the two-lever drug discrimination paradigm, in rats trained to discriminate saline from ip injections of LSD tartrate (0.08 mg/kg). Compounds will also be examined for affinity at the serotonin 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2, alphal- and alpha2-adrenergic, and dopamine D1 and D2 receptors. Collaborative arrangements have been made to obtain functional measures of those compounds that have high affinity for the serotonin and dopamine receptor subtypes (effects on PI turnover and cAMP). For the lysergamides, conformational energy calculations will be performed, and pKa and log P values will also be determined. Hallucinogenic lysergamides have not been adequately studied in the past and it is anticipated that some quantitative combination of variables for the lysergamides, and a consideration of the conformational energies, may allow correlation with the in vivo behavioral potency, thus identifying the relative importance and the nature of the interaction of LSD-like ligands with the various monoamine receptors. A particular power of this approach is the use of diastereomeric lysergamides with chiral amide substituents. The two synthetic partial ergoline analogues will be used to test the hypotheses that: (1) a 2,3-dihydrobenzofuran can serve as an effective bioisostere for an indole and, (2) that ergolines may undergo a D-ring inversion on' binding to some monoamine receptors to present the unshared electron pair of the amino group on the upper, or beta-face of the ergoline molecule. These studies will lead to a greater understanding of the nature of the ligand-receptor interaction for the monoamine receptors studied, as well as to a better understanding of the relative importance of these particular monoamine receptors in the action of LSD and other hallucinogens.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002189-15
Application #
2116513
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1992-07-15
Project End
1996-06-30
Budget Start
1994-07-01
Budget End
1996-06-30
Support Year
15
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Purdue University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
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
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
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
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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