Synthesis and pharmacological comparison of dimethylheptyl and pentyl analogs of anandamide

H H Seltzman, Denise N. Fleming, B F Thomas, A F Gilliam, D S McCallion, Roger Guy Pertwee, D R Compton, Billy R. Martin

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Abstract

(Dimethylheptyl)anandamide [(16,16-cimethyldocosa-cis-5,8,11,14-tetraenoyl)ethanolamine] (17a) and its amide analogs were synthesized by Wittig coupling of a ylide derived from a fragment of arachidonic acid. These amides were compared to the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide, 2a) and its amide analogs in pharmacological assays for potential enhancement of cannabimimetic activities. The receptor affinity to rat brain membranes of the dimethylheptyl (DMH) analogs increased by an order of magnitude in most comparisons to the corresponding anandamides in displacement assays versus the cannabinoid agonist [H-3]CP 55,940 or antagonist [H-3]SR141716A, for which rank order differences in affinity were observed. An order of magnitude enhancement of potency with comparable or higher efficacy in behavioral assays in the mouse tetrad of tests of cannabinoid activity was observed in 17a versus 2a. In contrast, no enhancement in potency for the pentyl to DMH side chain exchange was seen in the mouse vas deferens assay. The data indicate a structural equivalence between classical plant cannabinoids and 2a as well as different receptor-ligand interactions that characterize multiple receptor sites or binding modes.

Original languageEnglish
Pages (from-to)3626-3634
Number of pages9
JournalJournal of Medicinal Chemistry
Volume40
Issue number22
DOIs
Publication statusPublished - 24 Oct 1997

Keywords

  • CANNABINOID RECEPTOR-BINDING
  • ARACHIDONIC-ACID
  • BRAIN CONSTITUENT
  • CROSS-TOLERANCE
  • HIGH-AFFINITY
  • VAS-DEFERENS
  • RAT-BRAIN
  • IN-VIVO
  • AGONIST
  • MICE

Cite this

Seltzman, H. H., Fleming, D. N., Thomas, B. F., Gilliam, A. F., McCallion, D. S., Pertwee, R. G., Compton, D. R., & Martin, B. R. (1997). Synthesis and pharmacological comparison of dimethylheptyl and pentyl analogs of anandamide. Journal of Medicinal Chemistry, 40(22), 3626-3634. https://doi.org/10.1021/jm9702950