Drug discrimination and receptor binding studies of N-isopropyl lysergamide derivatives.
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 ED50 two to three times larger than that of LSD except for DIPLA, which had an ED50 about eightfold greater. Similarly, all the compounds displaced [125I](R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([125I]DOI) from rat cortical homogenates and displaced [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) from rat hippocampal homogenates with KI 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-HT2 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-HT1A and 5-HT2 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.
Huang
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Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
Marona-Lewicka
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Pfaff
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Nichols
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D006213:Hallucinogens / Q000494:pharmacology; D007457:Iodine Radioisotopes; D007650:Ketanserin / Q000378:metabolism; D008238:Lysergic Acid Diethylamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012055:Reinforcement Schedule
D000662:Amphetamines; D006213:Hallucinogens; D007457:Iodine Radioisotopes; C031182:LSD receptor; D011985:Receptors, Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D008238:Lysergic Acid Diethylamide; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine