Further studies on oxygenated tryptamines with LSD-like activity incorporating a chiral pyrrolidine moiety into the side chain

The enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, an d 3-(N-methylpyrrolidin-2-ylmethyl)-4-hydoxyindole, 3, were prepared using an asymmetric synthesis that employed (+)- or (-)-proline. A new approach w as developed that had certain advantages over the synthesis originally repo rted 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 asses s the affinity of compounds for the 5-HT2A receptor labeled with the agonis t ligand [I-125]DOI and the antagonist ligand [H-3]MDL100907. Two-lever dru g discrimination assays in rats trained to discriminate either LSD or DOI f rom saline were employed to assess the hallucinogen-like behavioral propert ies of these rigid tryptamine analogues. The receptor binding assay results clearly demonstrated a stereochemical preference for the R enantiomers tha t 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 enant iomers were virtually identical for both 1 and 3 at the agonist-labeled rec eptor, while racemic 4 and 5 had about one-tenth the affinity. The drug dis crimination data in both LSD- and DOI-trained rats paralleled the binding d ata using [I-125]DOI displacement. Both (R)-1 and (R)-3 are about equipoten t, comparable to DOI in activity but about 10-fold less potent than LSD. Co mpound 4 produced only partial substitution, even at a dose nearly 5-fold h igher than for (R)-1. Based on conformational energies, it seems doubtful t hat these compounds bind to the 5-HT2A receptor in an ergoline-like conform ation. The results also suggest that both 1 and 3 would possess LSD-like ps ychopharmacology in humans.