Antinociceptive activity of chemical congeners of improgan: optimization of side chain length leads to the discovery of a new, potent, non-opioid analgesic

L.H. Hough, I.J.P. de Esch, Elwin Janssen, J.R. Phillips, K. Svokos, B. Kern, J. Trachler, M.E. Abood, R. Leurs, J.B. Nalwalk

Research output: Contribution to JournalArticleAcademicpeer-review


Improgan is a chemical congener of the H2 antagonist cimetidine which shows the profile of a highly effective analgesic when administered
directly into the CNS. Although the improgan receptor is unknown, improgan activates analgesic pathways which are independent of opioids, but
may utilize cannabinoid mechanisms. To discover selective, potent, improgan-like drugs, seven compounds chemically related to improgan were
synthesized and tested for antinociceptive activity in rats after intracerebroventricular (icv) administration. Among a series of improgan congeners
in which the alkyl chain length of improgan ((eCH2)3e) was varied, five compounds showed full agonist antinociceptive activity with
potencies greater than that of improgan. VUF5420 (containing (eCH2)4e, EC50 ¼ 86.1 nmol) produced maximal antinociceptive activity after
doses which showed no motor impairment or other obvious toxicity, and was 2.3-fold more potent than improgan (EC50 ¼ 199.5 nmol). As
found previously with improgan, VUF5420-induced antinociception was unaffected by administration of the opioid antagonist naltrexone,
but was inhibited by the CB1 antagonist SR141716A, suggesting a non-opioid, cannabinoid-related analgesic action. However, VUF5420
showed very low affinity (Kd z 10 mM) on CB1-receptor activation of 35S-GTPgS binding, indicating that this drug does not directly interact
with the CB1 receptor in vivo. The present results show that VUF5420 is a high potency, improgan-like, non-opioid analgesic which may
indirectly activate cannabinoid pain-relieving mechanisms.
Original languageEnglish
Pages (from-to)447-456
Number of pages10
Issue number3
Early online date23 Jun 2006
Publication statusPublished - Sept 2006


  • Analgesics/chemical synthesis
  • Analgesics, Non-Narcotic/chemical synthesis
  • Animals
  • Behavior, Animal/drug effects
  • Cannabinoid Receptor Antagonists
  • Cell Line
  • Cimetidine/analogs & derivatives
  • Dose-Response Relationship, Drug
  • Guanosine 5'-O-(3-Thiotriphosphate)/pharmacokinetics
  • Humans
  • Injections, Intraventricular/methods
  • Male
  • Pain Measurement/drug effects
  • Pain Threshold/drug effects
  • Piperidines/pharmacology
  • Protein Binding/drug effects
  • Pyrazoles/pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time/drug effects
  • Receptors, Cannabinoid/drug effects
  • Rimonabant
  • Sulfur Isotopes/pharmacokinetics


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