Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain Madina Gerasimov, † Danuta Marona-Lewicka, Deborah M. Kurrasch-Orbaugh, Amjad M. Qandil, and David E. Nichols* Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907 Received June 24, 1999 The enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, and 3-(N-meth- ylpyrrolidin-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 displace- ment. 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. Introduction A number of studies have examined conformational restriction of the 3-(2-aminoethyl) side chain of serotonin as an approach to 5-HT analogues with receptor subtype selectivity. 1-5 Introduction of a stereocenter R to the amine nitrogen of serotonin, while also conformationally restricting the C-N bond of the aminoethyl side chain by incorporating it into a pyrrolidine ring, affords compounds that serve as useful chiral probes of 5-HT receptors. Macor et al. 1 first reported that (R)-(+)-3-(N- methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, had approximately 30-fold higher affinity than the S enan- tiomer at 5-HT 2A receptors and was as efficacious as serotonin in stimulating phosphatidylinositol (PI) turn- over in rat cortical slices. For many years we have been exploring the structure- activity relationships of hallucinogens and other cen- trally active substances that interact with serotonin receptors. Because the 5-HT 2A receptor is believed to be the primary target for hallucinogenic agents, the report by Macor et al. 1 prompted us to study the analogous conformationally constrained 4-hydroxy compounds re- lated to the naturally occurring hallucinogen psilocin. We were also curious as to whether transposing the oxygen substituent from the 5 to the 4 position in the tryptamines would have an effect on stereoselectivity at the 5-HT 2A receptor. We had previously found that the S isomer of 5-methoxy-R-methyltryptamine, 2, had higher affinity than the R isomer at both the serotonin 5-HT 1B and 5-HT 2 sites. 6 This selectivity was reversed, however, for 4-oxygenated R-methyltryptamines at the 5-HT 1B site. The present series of compounds was designed to elucidate further how constraining the side chain ster- eochemistry in 4-hydroxytryptamines affects activity at the serotonin 5-HT 2A receptor, compared with 5-meth- oxy-substituted analogues. Although the synthesis of the enantiomers of 1 is reported in the literature, 1 we describe here a new procedure for the preparation of this compound and its 4-hydroxy analogue 3. The synthesis of 5 employed a Michael reaction between the appropriate indole and N-methylmaleimide, as de- scribed previously for 4. 6 These compounds were evalu- ated for affinity at the 5-HT 2A receptor in rat prefrontal * Author for correspondence: Dr. David E. Nichols. Phone: (765)- 494-1461. Fax: (765)-494-1414. E-mail: drdave@pharmacy.purdue.edu. † Present address: Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973. 4257 J. Med. Chem. 1999, 42, 4257-4263 10.1021/jm990325u CCC: $18.00 © 1999 American Chemical Society Published on Web 09/16/1999