Effect of a Chiral 4-Alkyl Substituent in Hallucinogenic Amphetamines

Robert Oberlender, P. V. Ramachandran, Michael P. Johnson, Xuemei Huang, David E. Nichols

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The potency of hallucinogenic amphetamine derivatives of the 1-(2,5-dimethoxy-4-alkylphenyl)-2-aminopropane type drops dramatically when the length of the 4-alkyl substituent exceeds propyl or when the substituent is branched. This investigation was directed toward evaluating changes in behavioral and biochemical pharmacology resulting from introducing chirality into the 4-alkyl group of such analogues. Two diastereoisomeric derivatives of this class containing a 4-CR or S)-2-butyl substituent, 11a,b, respectively, were studied. A slight but nonsignificant potency difference in d-lysergic acid diethylamide tartrate (LSD)-like discriminative stimulus properties and equal affinity for [125I]-(R)(2,5-dimethoxy-4-iodophenyl)isopropylamme-labeled serotonin 5-HT2A/C radioligand-binding sites were observed. Thus, the portion of the receptor that interacts with the 4-alkyl substituent on hallucinogenic amphetamines does not present a highly asymmetric environment to the ligand. However, since both test drugs had higher binding affinity but lower LSD-like behavioral potency than the prototype compound with a 4-methyl group ((2,5-dimethoxy-4-methylphenyl)isopropylamine, 2), 11a,b may differ in their receptor agonist efficacy from more behaviorally active compounds such as 2.

Original languageEnglish (US)
Pages (from-to)3593-3601
Number of pages9
JournalJournal of Medicinal Chemistry
Volume38
Issue number18
DOIs
StatePublished - Sep 1 1995

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Amphetamines
Lysergic Acid Diethylamide
Amphetamine
Serotonin
Binding Sites
Pharmacology
Ligands
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Oberlender, R., Ramachandran, P. V., Johnson, M. P., Huang, X., & Nichols, D. E. (1995). Effect of a Chiral 4-Alkyl Substituent in Hallucinogenic Amphetamines. Journal of Medicinal Chemistry, 38(18), 3593-3601. https://doi.org/10.1021/jm00018a019
Oberlender, Robert ; Ramachandran, P. V. ; Johnson, Michael P. ; Huang, Xuemei ; Nichols, David E. / Effect of a Chiral 4-Alkyl Substituent in Hallucinogenic Amphetamines. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 18. pp. 3593-3601.
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Oberlender, R, Ramachandran, PV, Johnson, MP, Huang, X & Nichols, DE 1995, 'Effect of a Chiral 4-Alkyl Substituent in Hallucinogenic Amphetamines', Journal of Medicinal Chemistry, vol. 38, no. 18, pp. 3593-3601. https://doi.org/10.1021/jm00018a019

Effect of a Chiral 4-Alkyl Substituent in Hallucinogenic Amphetamines. / Oberlender, Robert; Ramachandran, P. V.; Johnson, Michael P.; Huang, Xuemei; Nichols, David E.

In: Journal of Medicinal Chemistry, Vol. 38, No. 18, 01.09.1995, p. 3593-3601.

Research output: Contribution to journalArticle

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AB - The potency of hallucinogenic amphetamine derivatives of the 1-(2,5-dimethoxy-4-alkylphenyl)-2-aminopropane type drops dramatically when the length of the 4-alkyl substituent exceeds propyl or when the substituent is branched. This investigation was directed toward evaluating changes in behavioral and biochemical pharmacology resulting from introducing chirality into the 4-alkyl group of such analogues. Two diastereoisomeric derivatives of this class containing a 4-CR or S)-2-butyl substituent, 11a,b, respectively, were studied. A slight but nonsignificant potency difference in d-lysergic acid diethylamide tartrate (LSD)-like discriminative stimulus properties and equal affinity for [125I]-(R)(2,5-dimethoxy-4-iodophenyl)isopropylamme-labeled serotonin 5-HT2A/C radioligand-binding sites were observed. Thus, the portion of the receptor that interacts with the 4-alkyl substituent on hallucinogenic amphetamines does not present a highly asymmetric environment to the ligand. However, since both test drugs had higher binding affinity but lower LSD-like behavioral potency than the prototype compound with a 4-methyl group ((2,5-dimethoxy-4-methylphenyl)isopropylamine, 2), 11a,b may differ in their receptor agonist efficacy from more behaviorally active compounds such as 2.

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