Two thienopyrrole compounds, designed as structural replacements for the indole ring in N,N-dimethyltryptamine (DMT), were synthesized and tested. Neither compound produced LSD-like effects in rats trained to discriminate LSD or DOI, even at high doses. However, both fully substituted for a 5-HT1A receptor agonist and caused behaviors consistent with 5-HT1A activation, such as serotonin syndrome and salivation. At the 5-HT2A receptor, one compound had twice the affinity of the other, while at 5-HT2B and 5-HT2C receptors the pattern reversed. The thienopyrrole replacement thus failed to mimic DMT's activity at 5-HT2 receptors but enhanced activity at the 5-HT1A receptor, indicating that serotonin receptor subtypes respond differently to subtle electronic changes in the aromatic ring system.
Amides of d-lysergic acid with 3-pentyl, (R)- and (S)-2-pentyl, 2-hexyl, and 2-heptyl substituents were synthesized and tested for LSD-like activity. (R)-lysergamides bound more strongly than (S)-amides to 5-HT2A and 5-HT1A receptors in rat brain tissue. As the amide alkyl chain lengthened from pentyl to heptyl, (R)-isomer affinity for 5-HT2A sites decreased, while affinity for 5-HT1A peaked with (R)-2-hexyllysergamide. In rats trained to discriminate LSD from saline, (R)-alkylamides produced stronger LSD-like effects than (S)-isomers, but longer chains reduced activity, with (R)-hexylamide only partially substituting for LSD. Both isomers acted as potent 5-HT2A agonists, but (R)-pentyllysergamide stimulated phosphoinositide hydrolysis about 20 times more than the (S)-form.