title: Antinociceptive activity of chemical congeners of improgan: optimization of side chain length leads to the discovery of a new, potent, non-opioid analgesic.
abstract: 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 ((-CH2)3-) was varied, five compounds showed full agonist antinociceptive activity with potencies greater than that of improgan. VUF5420 (containing (-CH2)4-, EC50 = 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 = 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 approximately 10 microM) on CB1-receptor activation of 35S-GTPgammaS 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.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College MC-136, Albany, NY 12208, USA. houghl@mail.amc.edu
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Hough
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Elwin
authors.initials: E
authors.lastname: Janssen
authors.forename: James
authors.initials: J
authors.lastname: Phillips
authors.forename: Konstantina
authors.initials: K
authors.lastname: Svokos
authors.forename: Brian
authors.initials: B
authors.lastname: Kern
authors.forename: Jennifer
authors.initials: J
authors.lastname: Trachler
authors.forename: Mary E
authors.initials: ME
authors.lastname: Abood
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Julia W
authors.initials: JW
authors.lastname: Nalwalk
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists; D002460:Cell Line; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D010147:Pain Measurement / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000502:physiology; D000077285:Rimonabant; D013460:Sulfur Isotopes / Q000493:pharmacokinetics
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C099531:SKF 92374; D013460:Sulfur Isotopes; C515419:VUF5420; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002927:Cimetidine; D000077285:Rimonabant