Conformationally restricted bioisosteres of mescaline's methoxy groups—dihydrobenzofuran (8) and tetrahydrobenzodifuran (9)—were synthesized and tested against mescaline (1) in drug discrimination assays in rats trained to discriminate LSD from saline. Neither 8 nor 9 substituted for LSD: only 50% of rats given 8 and 29% given 9 selected the drug lever, whereas mescaline fully substituted (ED50 = 33.5 mumol/kg). All compounds showed micromolar affinity for 5-HT1A and 5-HT2A receptors in rat brain homogenate, but rank order of affinities at 5-HT2A sites reversed their behavioral potency. At 5-HT2A receptors, 8 and 9 were less efficacious (61% and 45% of maximal response), while all compounds matched serotonin's efficacy at 5-HT2C receptors.
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.