Journal of Pharmacology and Experimental Therapeutics
September 1, 1988
Elaine Sanders‐bush, Kevin D. Burris, Karen M. Knoth
155 citations
The hallucinogens DOM and LSD act as partial agonists at serotonin 5-HT-2 receptors in rat cerebral cortex and at 5-HT-1c receptors in rat choroid plexus, stimulating phosphoinositide hydrolysis. In cortex, DOM and LSD produced maximum responses 76% and 25% of serotonin's maximum, respectively, with LSD 500 times more potent than DOM. LSD partially blocked serotonin's effect, consistent with partial agonism. In choroid plexus, DOM and LSD reached 67% and 34% of serotonin's maximum, with LSD 50 times more potent than DOM. These effects were blocked by specific serotonin antagonists, supporting the role of 5-HT-2 and 5-HT-1c receptors in mediating hallucinogenic actions.
Journal of Medicinal Chemistry
September 1, 1997
Aaron Monte, Steve R. Waldman, Danuta Marona‐lewicka et al.
89 citations
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.
Journal of Neurochemistry
June 18, 2004
Charles D. Nichols, Elaine Sanders‐bush
62 citations
Lysergic acid diethylamide (LSD) increases the expression of three specific genes in the mammalian prefrontal cortex: C/EBP-beta, a transcription factor; MKP-1, indicating activation of the MAP kinase pathway; and ILAD-1, which shows sequence similarity to arrestins. These expression changes are partially mediated through LSD interactions at 5-HT2A serotonin receptors. Evidence suggests alternative splicing at the ILAD-1 locus, with different splice isoforms responding differently at the transcriptional level to LSD. These findings help build a more complete picture of the complex intracellular events initiated by hallucinogens.
Journal of Medicinal Chemistry
March 1, 1995
Aaron Monte, Danuta Marona‐lewicka, Arthi Kanthasamy et al.
25 citations
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.