Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain
| Autor: | Danuta Marona-Lewicka, Deborah M. Kurrasch-Orbaugh, and Amjad M. Qandil, Madina Gerasimov, David E. Nichols |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Male
Indoles Pyrrolidines Stereochemistry In Vitro Techniques Binding Competitive Chemical synthesis Pyrrolidine Discrimination Learning Rats Sprague-Dawley Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Radioligand medicine Animals Receptor Serotonin 5-HT2A Enantioselective synthesis Stereoisomerism Ligand (biochemistry) Tryptamines Frontal Lobe Rats Lysergic Acid Diethylamide chemistry Receptors Serotonin Psilocin Molecular Medicine Enantiomer medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 42:4257-4263 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm990325u |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|