Two new compounds related to hallucinogenic amphetamines were synthesized and tested in rats trained to discriminate LSD from saline, and for their ability to bind to serotonin 5-HT2 receptors in rat brain tissue. The compounds, which contain a rigid dihydrofuran ring, showed activity similar to their more flexible counterparts. Adding a bromine atom to the compounds contributed 2.4–3.2 kcal/mol of binding energy, 2–3 times more than expected from hydrophobic binding alone, suggesting that the bromine's effect cannot be explained solely by its hydrophobicity and that an unknown receptor interaction is involved.
Both the (R)- and (S)-2-butylamides of d-lysergic acid fully substituted for LSD in rats trained to discriminate LSD from saline, and both showed very high affinity for 5-HT2 and 5-HT1A receptors. The R isomer was significantly more potent than the S isomer in both behavioral and binding assays. Molecular mechanics modeling indicated that the (R)-2-butylamide adopts a conformation similar to LSD, whereas the (S)-2-butylamide does not. These results suggest that the stereochemistry of the amide substituent critically influences hallucinogenic activity, possibly through stereoselective interactions with a hydrophobic receptor region or by inducing conformational changes elsewhere in the molecule.