CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

Lindsay B Hough, Julia W Nalwalk, James G Phillips, Brian Kern, Zhixing Shan, Mark P Wentland, Iwan J P de Esch, Elwin Janssen, Travis Barr, Rebecca Stadel

Research output: Contribution to JournalArticleAcademicpeer-review


Improgan, a chemical congener of cimetidine, is a highly effective non-opioid analgesic when injected into the CNS. Despite extensive characterization, neither the improgan receptor, nor a pharmacological antagonist of improgan has been previously described. Presently, the specific binding of [(3)H]cimetidine (3HCIM) in brain fractions was used to discover 4(5)-((4-iodobenzyl)thiomethyl)-1H-imidazole, which behaved in vivo as the first improgan antagonist. The synthesis and pharmacological properties of this drug (named CC12) are described herein. In rats, CC12 (50-500nmol, i.c.v.) produced dose-dependent inhibition of improgan (200-400nmol) antinociception on the tail flick and hot plate tests. When given alone to rats, CC12 had no effects on nociceptive latencies, or on other observable behavioral or motor functions. Maximal inhibitory effects of CC12 (500nmol) were fully surmounted with a large i.c.v. dose of improgan (800nmol), demonstrating competitive antagonism. In mice, CC12 (200-400nmol, i.c.v.) behaved as a partial agonist, producing incomplete improgan antagonism, but also limited antinociception when given alone. Radioligand binding, receptor autoradiography, and electrophysiology experiments showed that CC12's antagonist properties are not explained by activity at 25 sites relevant to analgesia, including known receptors for cannabinoids, opioids or histamine. The use of CC12 as an improgan antagonist will facilitate the characterization of improgan analgesia. Furthermore, because CC12 was also found presently to inhibit opioid and cannabinoid antinociception, it is suggested that this drug modifies a biochemical mechanism shared by several classes of analgesics. Elucidation of this mechanism will enhance understanding of the biochemistry of pain relief.

Original languageEnglish
Pages (from-to)1244-1255
Number of pages12
Issue number5
Early online date20 Jan 2007
Publication statusPublished - Apr 2007


  • Analgesics, Opioid/pharmacology
  • Animals
  • Autoradiography
  • Benzoxazines/pharmacology
  • Binding Sites/drug effects
  • Cimetidine/analogs & derivatives
  • Dose-Response Relationship, Drug
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology
  • Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology
  • Histamine/pharmacology
  • Histamine H2 Antagonists/metabolism
  • Imidazoles/chemical synthesis
  • Indicators and Reagents
  • Injections, Intraventricular
  • Ligands
  • Male
  • Membranes/drug effects
  • Mice
  • Morpholines/pharmacology
  • Naloxone/pharmacology
  • Naphthalenes/pharmacology
  • Narcotic Antagonists/pharmacology
  • Pain Measurement/drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Histamine H2/drug effects
  • Sulfides/chemical synthesis


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