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

Xuemei Huang, Danuta Marona-Lewicka, Robert C. Pfaff, David E. Nichols

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)667-673
Number of pages7
JournalPharmacology, Biochemistry and Behavior
Volume47
Issue number3
DOIs
StatePublished - Jan 1 1994

Fingerprint

Drug Receptors
Lysergic Acid Diethylamide
Derivatives
Rats
8-Hydroxy-2-(di-n-propylamino)tetralin
Conformations
Serotonin 5-HT2 Receptor Agonists
lysergamide
Ketanserin
Molecular modeling
Amides
Assays
Substitution reactions
Binding Sites

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

Cite this

Huang, Xuemei ; Marona-Lewicka, Danuta ; Pfaff, Robert C. ; Nichols, David E. / Drug discrimination and receptor binding studies of N-isopropyl lysergamide derivatives. In: Pharmacology, Biochemistry and Behavior. 1994 ; Vol. 47, No. 3. pp. 667-673.
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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 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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Drug discrimination and receptor binding studies of N-isopropyl lysergamide derivatives. / Huang, Xuemei; Marona-Lewicka, Danuta; Pfaff, Robert C.; Nichols, David E.

In: Pharmacology, Biochemistry and Behavior, Vol. 47, No. 3, 01.01.1994, p. 667-673.

Research output: Contribution to journalArticle

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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.

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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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