title: CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist.
abstract: 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.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA. houghl@mail.amc.edu
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Hough
authors.forename: Julia W
authors.initials: JW
authors.lastname: Nalwalk
authors.forename: James G
authors.initials: JG
authors.lastname: Phillips
authors.forename: Brian
authors.initials: B
authors.lastname: Kern
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Shan
authors.forename: Mark P
authors.initials: MP
authors.lastname: Wentland
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Elwin
authors.initials: E
authors.lastname: Janssen
authors.forename: Travis
authors.initials: T
authors.lastname: Barr
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stadel
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D048588:Benzoxazines / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000378:metabolism*; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007202:Indicators and Reagents; D007276:Injections, Intraventricular; D008024:Ligands; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D013440:Sulfides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C521071:4(5)-((4-iodobenzyl)thiomethyl)-1H-imidazole; D000701:Analgesics, Opioid; D048588:Benzoxazines; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D007202:Indicators and Reagents; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D009292:Narcotic Antagonists; D011970:Receptors, Histamine H2; C099531:SKF 92374; D013440:Sulfides; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D002927:Cimetidine; D006632:Histamine