title: Antinociceptive activity of derivatives of improgran and burimamide.
abstract: Improgan, a compound related to H2 and H3 antagonists, induces antinociception in rodents after intraventricular administration. Characteristics of improgan and its congeners include: (a) morphine-like antinociception on thermal and mechanical tests in two species; (b) no impairment of motor coordination or locomotor activity; (c) evidence for a novel, nonopioid mechanism that is independent of known histamine receptors; (d) lack of tolerance with daily dosing; and (e) unique structure-activity relationships (SARs). Presently, the antinociceptive activity of several new derivatives of improgan was investigated in rats. Among compounds similar to burimamide, VUF4577 (possessing a two-carbon side chain) and VUF4582 (an N-phenyl derivative of VUF4577) induced complete, dose- and time-dependent antinociception on the hot-plate and tail-flick tests with no behavioral side effects. These compounds (with ED50 values of 71-117 nmol) were approximately twice as potent as burimamide itself (a four-carbon derivative). Two other derivatives in which the thiourea group (C=S, known to cause human toxicity) was replaced by either nitroethene (C=CH-NO2, VUF5405) or urea (C=O, VUF5407) also showed effective, potent antinociception on both assays. The latter compound is the most potent improgan-like drug discovered to date (ED50 = 71 nmol). Furthermore, positional isomers of antinociceptive compounds either lacked activity (VUF5394) or induced toxicity (VUF5393), revealing a high degree of pharmacological specificity. Although the mechanism of improgan antinociception remains unknown, the present results show promise for the further development of safe, effective, and potent pain-relieving compounds.
authors.affiliation: Department of Pharmacology and Neuroscience, Albany Medical College, NY 12208, USA. houghl@mail.amc.edu
authors.forename: L B
authors.initials: LB
authors.lastname: Hough
authors.forename: J W
authors.initials: JW
authors.lastname: Nalwalk
authors.forename: R
authors.initials: R
authors.lastname: Leurs
authors.forename: W M
authors.initials: WM
authors.lastname: Menge
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D002049:Burimamide / Q000494:pharmacology*; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D018712:Analgesics, Non-Narcotic; D006635:Histamine H2 Antagonists; D018100:Receptors, Histamine H3; C099531:SKF 92374; D002927:Cimetidine; D002049:Burimamide