Both enantiomers of 2-LSP show affinity for the serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, but (R)-2-LSP shows far greater affinity for these receptors in comparison.[3][2][7][6] (R)-2-LSP had about the same affinity as LSD for the serotonin 5-HT2A receptor (Ki = 4.5–10nM; K0.5 = 0.99–1.0nM), but had 0.8- to 9-fold higher affinity than LSD for the serotonin 5-HT1A receptor (Ki = 0.6–1.4nM; K0.5 = 0.37nM).[3][2][1][7][5][6] Both (R)- and (S)-2-LSP act as full agonists of the serotonin 5-HT2A receptor, but (R)-LSP is nearly 20-fold more potent than (S)-LSP in this regard EC50Tooltip half-maximal effective concentration (EmaxTooltip maximal efficacy) = 5.4nM (100%) and 91nM (100%), respectively).[3][2][7] Both enantiomers are also serotonin 5-HT2C receptor agonists, with (R)-LSP likewise being much more active than (S)-LSP.[7] (R)-2-LSP fully substituted for LSD in rodent drug discrimination tests, with about half the potency of LSD.[1][2][3][7][5] Conversely, (S)-2-LSP did not substitute for LSD in these tests.[1][2][3][7]
123456Nichols DE (2018). Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. Vol.36. pp.1–43. doi:10.1007/7854_2017_475. ISBN978-3-662-55878-2. PMID28401524. This approach was extended to study of a series of chiral 2-aminoalkane amides of lysergic acid, with the alkyl group extended from butyl to heptyl (Monte et al. 1995). Using [3 H]ketanserin displacement from rat frontal cortex homogenate to measure 5-HT2A receptor affinity, the lysergamide with the R-configuration in the secondary alkyl amide group had higher affinity in every case than the one with the S configuration. As the chain length increased affinity decreased, with the R-2-heptylamide having a Ki of only 80 nM. The pentyl isomers of 26 were the only compounds tested in functional assays, where each isomer proved to be a full agonist in the PI hydrolysis assay, but the S-isomer was less potent (see Table 1). Surprisingly, however, extending the length of the 2-alkyl group of the amide increased 5-HT1A receptor affinity, with the R-2-hexyl substituted amide having a Ki of 0.32 nM! Clearly, the 5-HT1A receptor has greater tolerance for bulk attached to the amide. Tests in rats trained to discriminate LSD from saline showed that full substitution occurred with the R-2-pentyl lysergamide 26, but not with the S-pentyl, hexyl, or heptyl compounds. In vitro affinities observed at the rat 5-HT2A receptor parallel these in vivo results.
1234Nichols DE, Monte A, Huang X, Marona-Lewicka D (1996). "Stereoselective pharmacological effects of lysergic acid amides possessing chirality in the amide substituent". Behavioural Brain Research. 73 (1–2): 117–119. doi:10.1016/0166-4328(96)00080-0. PMID8788487. The most potent LSD-like compound, with greatest similarity to LSD itself in all the bioassays was the lysergamide prepared from (R)-2- aminobutane (see Table 2). In vivo activity in the drug discrimination assay rapidly drops off when the alkyl group is extended to the next higher homolog, the (R)- 2-aminopentane derivative, even though affinity for the ketanserin-labeled 5-HT2A receptor is comparable to that of LSD, and affinity for the 5-HT1A receptor is increased about 7- or 8-fold.
123456789Monte AP, Marona-Lewicka D, Kanthasamy A, Sanders-Bush E, Nichols DE (March 1995). "Stereoselective LSD-like activity in a series of d-lysergic acid amides of (R)- and (S)-2-aminoalkanes". Journal of Medicinal Chemistry. 38 (6): 958–966. doi:10.1021/jm00006a015. PMID7699712.
