Synthesis and Evaluation of Substituted 2-Phenylcyclobutylamines as Analogues of Hallucinogenic Phenethylamines

Lack of LSD-like Biological Activity

David E. Nichols, Kiran P. Jadhav, Robert A. Oberlender, Joseph E. Zabik, Josef F. Bossart, Akihiko Hamada, Duane Miller

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

cis-and tnms-2-(2, 4, 5-trimethoxyphenyl)cyclobutylamine and irans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg. For both of the trans compounds, partial generalization of the LSD cue occurred at doses of 5 mg/kg or greater. In contrast, complete generalization occurred with trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. The ED50 for this compound and the doses of the trans cyclobutyl homologues at which significant drug-appropriate responding occurred indicate that the latter are on the order of 50-75 times less potent than the cyclopropylamine analogue. The lack of generalization to the cyclobutylamines indicates either that their discriminative stimulus properties differ from LSD or that they lack discriminative effects.

Original languageEnglish (US)
Pages (from-to)1108-1111
Number of pages4
JournalJournal of Medicinal Chemistry
Volume27
Issue number9
DOIs
StatePublished - Jan 1 1984
Externally publishedYes

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Phenethylamines
Lysergic Acid Diethylamide
Stimulus Generalization
Pharmaceutical Preparations
Cues
Generalization (Psychology)

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and Evaluation of Substituted 2-Phenylcyclobutylamines as Analogues of Hallucinogenic Phenethylamines : Lack of LSD-like Biological Activity. / Nichols, David E.; Jadhav, Kiran P.; Oberlender, Robert A.; Zabik, Joseph E.; Bossart, Josef F.; Hamada, Akihiko; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 27, No. 9, 01.01.1984, p. 1108-1111.

Research output: Contribution to journalArticle

Nichols, David E. ; Jadhav, Kiran P. ; Oberlender, Robert A. ; Zabik, Joseph E. ; Bossart, Josef F. ; Hamada, Akihiko ; Miller, Duane. / Synthesis and Evaluation of Substituted 2-Phenylcyclobutylamines as Analogues of Hallucinogenic Phenethylamines : Lack of LSD-like Biological Activity. In: Journal of Medicinal Chemistry. 1984 ; Vol. 27, No. 9. pp. 1108-1111.
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abstract = "cis-and tnms-2-(2, 4, 5-trimethoxyphenyl)cyclobutylamine and irans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg. For both of the trans compounds, partial generalization of the LSD cue occurred at doses of 5 mg/kg or greater. In contrast, complete generalization occurred with trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. The ED50 for this compound and the doses of the trans cyclobutyl homologues at which significant drug-appropriate responding occurred indicate that the latter are on the order of 50-75 times less potent than the cyclopropylamine analogue. The lack of generalization to the cyclobutylamines indicates either that their discriminative stimulus properties differ from LSD or that they lack discriminative effects.",
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