Drug discrimination and receptor binding studies of N-isopropyl lysergamide derivatives

Abstract

N-Isopropyl (IPLA), N-methyl- N-isopropyl (MIPLA), N-ethyl- N-isopropyl (EIPLA), and N, N-diisopropyl (DIPLA) lysergamides were evaluated for lysergic acid diethylamide (LSD)-like activity. In rats trained to discriminate 0.08 mg/kg LSD tartrate from saline, each of the subject compounds completely substituted, with an ED 50 two to three times larger than that LSD except for DIPLA, which had an ED 50 about eightfold greater. Similarly, all the compounds displaced [ 125I](itR)-1-(2,5-dimethoxy-4-iodophenyl) -2-aminopropane ([ 125I]DOI) from rat cortical homogenates and displaced [ 3 H]8- hydroxy-2-( di-n- propylamino) tetralin ([ 3H]8-OH-DPAT) from rat hippocampal homogenates with K I values similar to those of LSD, again with the exception of DIPLA, which had about nine- and fourfold lower affinities, respectively. Interestingly, all the compounds had four- to fivefold lower affinities than LSD in displacing [ 3H]ketanserin from 5-HT 2 binding sites. Molecular modeling studies found that all the compounds had low energy conformations similar to LSD. No correlation between the activity of the compounds and the preferred conformation of the amide substituents was apparent. In summary, N-alkyl- N-isopropyl analogs of LSD retain LSD-like activity in drug discrimination and 5-HT 1A and 5-HT 2 agonist binding assays only until the N-alkyl substitution is as large as ethyl; LSD-like activity dramatically drops when the second alkyl substituent is N-isopropyl.