DRUG DISCRIMINATION AND RECEPTOR-BINDING STUDIES OF N-ISOPROPYL LYSERGAMIDE DERIVATIVES

N-Isopropyl (IPLA), N-methyl-N-isopropyl (MIPLA), N-ethyl-N-isopropyl (EIPLA), and N,N-diisopropyl (DIPLA) lysergamides were evaluated for l ysergic acid diethylamide (LSD)-like activity. In rats trained to disc riminate 0.08 mg/kg LSD tartrate from saline, each of the subject comp ounds completely substituted, with an ED(50) two to three times larger than that of LSD except for DIPLA, which had an ED(50) about eightfol d greater. Similarly, all the compounds displaced ](R)-1-(2,5-dimethox y-4-iodophenyl)-2-aminopropane ([I-125]DOI) from rat cortical homogena tes and displaced [H-3]8-hydroxy-2-(di-npropylamino)tetralin ([H-3]8-O H-DPAT) from rat hippocampal homogenates with K-I values similar to th ose of LSD, again with the exception of DIPLA. which had about nine- a nd fourfold lower affinities, respectively. Interestingly, all the com pounds had four- to fivefold lower affinities than LSD in displacing [ H-3]ketanserin from 5-HT2 binding sites. Molecular modeling studies fo und that all the compounds had low energy conformations similar to LSD . No correlation between the activity of the compounds and the preferr ed conformation of the amide substituents was apparent. In summary, N- alkyl-Nisopropyl analogs of LSD retain LSD-like activity in drug discr imination and 5-HT1A and 5-HT2 agonist binding assays only until the N -alkyl substitution is as large as ethyl; LSD-like activity dramatical ly drops when the second alkyl substituent is N-isopropyl.