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.