Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain
Madina R. Gerasimov, Danuta Marona‐lewicka, Deborah Kurrasch‐orbaugh, Amjad M. Qandil, David E. Nichols
Journal of Medicinal Chemistry September 16, 1999 DOI: 10.1021/jm990325u (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Topics | LSD |
| Keywords | Enantiomer Stereochemistry Tryptamine Ligand biochemistry Moiety Pyrrolidine Chemical synthesis Partial agonist Radioligand Intrinsic activity Receptor |
| Citations | 15 |
| Key findings | The R enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole and 3-(N-methylpyrrolidin-2-ylmethyl)-4-hydroxyindole show 10-20-fold higher affinity for the 5-HT(2A) receptor than the S enantiomers and produce LSD-like behavioral effects in rats. |
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.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 4
- Lysergamides of Isomeric 2,4-Dimethylazetidines Map the Binding Orientation of the Diethylamide Moiety in the Potent Hallucinogenic Agent N,N-Diethyllysergamide (LSD) Journal of Medicinal Chemistry September 1, 2002
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice. ACS Chemical Neuroscience December 18, 2024
- Tryptamines as Ligands and Modulators of the Serotonin 5‑HT2A Receptor and the Isolation of Aeruginascin from the Hallucinogenic Mushroom Inocybe aeruginascens 2005