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Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine

Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine

  1. trptamene
    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-HT2A receptor labeled with the agonist ligand [125I]DOI and the antagonist
    ligand [3H]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 agonistlabeled
    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 [125I]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-HT2A receptor in an ergoline-like conformation. The results
    also suggest that both 1 and 3 would possess LSD-like psychopharmacology in humans.

    J. Med. Chem. 1999, 42, 4257-4263