title: Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives.
abstract: Dihydrobenzofuran and tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in the prototypical hallucinogen, mescaline (1). Thus, 4-(2-aminoethyl)-6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride (8) and 1-(8-methoxy-2,3,5,6-tetrahydrobenzo[1,2-b:5,4-b']difuran-4-yl)-2- aminoethane hydrochloride (9) were prepared and evaluated along with 1 for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). Also, 1, 8, and 9 were assayed for their ability to displace [3H]ketanserin from rat cortical homogenate 5-HT2A receptors and [3H]8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, these compounds were evaluated for their ability to compete for agonist and antagonist binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Finally, agonist efficacy was assessed by measurement of phosphoinositide hydrolysis in NIH 3T3 cells expressing the rat 5-HT2A or 5-HT2C receptors. Although 1 fully substituted for LSD in the DD assays (ED50 = 33.5 mumol/kg), neither 8 nor 9 substituted for LSD, with just 50% of the rats administered 8 selecting the drug lever, and only 29% of the rats administered 9 selecting the drug lever. All of the test compounds had micromolar affinity for the 5-HT1A and 5-HT2A receptors in rat brain homogenate. Curiously, the rank order of affinities of the compounds at 5-HT2A sites was opposite their order of potency in the behavioral assay. An evaluation for ability to stimulate phosphoinositide turnover as a measure of functional efficacy revealed that all the compounds were of approximately equal efficacy to serotonin in 5-HT2C receptors. At 5-HT2A receptors, however, 8 and 9 were significantly less efficacious, eliciting only 61 and 45%, respectively, of the maximal response. These results are consistent with the proposed mechanism of action for phenethylamine hallucinogens, that such compounds must be full agonists at the 5-HT2A receptor subtype. In contrast to the 2,5-dimethoxy-substituted phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable receptor activation.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Monte
authors.forename: S R
authors.initials: SR
authors.lastname: Waldman
authors.forename: D
authors.initials: D
authors.lastname: Marona-Lewicka
authors.forename: D B
authors.initials: DB
authors.lastname: Wainscott
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: E
authors.initials: E
authors.lastname: Sanders-Bush
authors.forename: D E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006213:Hallucinogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007928:Lethal Dose 50; D008238:Lysergic Acid Diethylamide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008635:Mescaline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D001572:Benzofurans; D006213:Hallucinogens; D007202:Indicators and Reagents; D010716:Phosphatidylinositols; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D008238:Lysergic Acid Diethylamide; D008635:Mescaline