TY - JOUR
T1 - Drug discrimination and receptor binding studies of N-isopropyl lysergamide derivatives
AU - Huang, Xuemei
AU - Marona-Lewicka, Danuta
AU - Pfaff, Robert C.
AU - Nichols, David E.
N1 - Funding Information:
This research was supported by U.S. Public Health Service grant DA02189 from the National Institute on Drug Abuse. R.C.P. thanks CAChe Scientific, Inc. for partial contributions of modeling hardware and software. We thank Stewart Frescas for synthesis of the IPLA, MIPLA, EIPLA, and DIPLA; Arthi Kanthasamy for excellent technical assistance with the binding experiments; and Matt Parker for helpful comments during the preparation of this article.
PY - 1994/3
Y1 - 1994/3
N2 - 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 ED50 two to three times larger than that LSD except for DIPLA, which had an ED50 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 [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.
AB - 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 ED50 two to three times larger than that LSD except for DIPLA, which had an ED50 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 [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.
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U2 - 10.1016/0091-3057(94)90172-4
DO - 10.1016/0091-3057(94)90172-4
M3 - Article
C2 - 8208787
AN - SCOPUS:0028316545
SN - 0091-3057
VL - 47
SP - 667
EP - 673
JO - Pharmacology, Biochemistry and Behavior
JF - Pharmacology, Biochemistry and Behavior
IS - 3
ER -