title: Further studies on oxygenated tryptamines with LSD-like activity incorporating a chiral pyrrolidine moiety into the side chain.
abstract: The enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, and 3-(N-methylpyrrolidin-2-ylmethyl)-4-hydoxyindole, 3, were prepared using an asymmetric synthesis that employed (+)- or (-)-proline. A new approach was developed that had certain advantages over the synthesis originally reported for the isomers of 1. (+/-)-3-(N-Methylpyrrolidin-3-yl)-4-hydroxyindole, 5, was also prepared as a rigid analogue of psilocin and compared with its 5-methoxy counterpart 4. Radioligand competition assays were used to assess the affinity of compounds for the 5-HT(2A) receptor labeled with the agonist ligand [(125)I]DOI and the antagonist ligand [(3)H]MDL100907. Two-lever drug discrimination assays in rats trained to discriminate either LSD or DOI from saline were employed to assess the hallucinogen-like behavioral properties of these rigid tryptamine analogues. The receptor binding assay results clearly demonstrated a stereochemical preference for the R enantiomers that did not discriminate the position of the oxygen function. The receptor is 10-20-fold more selective for the R isomers. The affinities of the R enantiomers were virtually identical for both 1 and 3 at the agonist-labeled receptor, while racemic 4 and 5 had about one-tenth the affinity. The drug discrimination data in both LSD- and DOI-trained rats paralleled the binding data using [(125)I]DOI displacement. Both (R)-1 and (R)-3 are about equipotent, comparable to DOI in activity but about 10-fold less potent than LSD. Compound 4 produced only partial substitution, even at a dose nearly 5-fold higher than for (R)-1. Based on conformational energies, it seems doubtful that these compounds bind to the 5-HT(2A) receptor in an ergoline-like conformation. The results also suggest that both 1 and 3 would possess LSD-like psychopharmacology in humans.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gerasimov
authors.forename: D
authors.initials: D
authors.lastname: Marona-Lewicka
authors.forename: D M
authors.initials: DM
authors.lastname: Kurrasch-Orbaugh
authors.forename: A M
authors.initials: AM
authors.lastname: Qandil
authors.forename: D E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D004193:Discrimination Learning / Q000187:drug effects; D005625:Frontal Lobe / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C122070:3-(N-methylpyrrolidin-2-ylmethyl)-4-hydroxyindole; D007211:Indoles; D011759:Pyrrolidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D014363:Tryptamines; C122069:3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole; D008238:Lysergic Acid Diethylamide