title: Histogranin-like antinociceptive and anti-inflammatory derivatives of o-phenylenediamine and benzimidazole.
abstract: Histogranin (HN)-like nonpeptides were designed and synthesized using benzimidazole (compound 1) and o-phenylenediamine (compounds 2-7) as scaffolds for the attachment of phenolic hydroxyl and basic guanidino pharmacophoric elements present in HN. The benzimidazole derivative N-5-guanidinopentanamide-(2R)-yl-2-(p-hydroxybenzyl)-5-carboxybenzimidazole (1) and the o-phenylenediamine derivative N-5-guanidinopentanamide-(2S)-yl-2-N-(p-hydroxyphenylacetyl) phenylenediamine (2) were more potent analgesics than HN in both the mouse writhing (5.5 and 3.5 as potent as HN, respectively) and tail-flick (11.8 and 8.0 as potent as HN, respectively) pain assays. Improvements in the potencies and times of action of compound 2 in the mouse writhing test were obtained by attaching carboxyl (6)or p-Cl-benzoyl (7) groups at position 4 of the (2R) o-phenylenediamine derivative (5). In rats, compounds 2 (80 nmol i.t.), 6 (36 nmol i.t.), and 7 (18 nmol i.t.) were effective in blocking both persistent inflammatory pain in the formalin test and hyperalgesia in the complete Freund adjuvant assay. Compounds 2, 6, and 7, but not compound 1 at 10 nmol (i.c.v.) also mimicked the HN (60 nmol i.c.v.) blockade of N-methyl-D-aspartate (NMDA)-induced convulsions in mice. Finally, in primary cultures of rat alveolar macrophages, HN and compounds 1, 2, 6, and 7 (10(-8) M) significantly blocked lipopolysaccharide-induced cyclooxygenase-2 induction and prostaglandin E(2) secretion. These studies indicate that both derivatives of benzimidazole and o-phenylenediamine mimic the in vivo antinociceptive and in vitro anti-inflammatory effects of HN, but the HN protection of mice against NMDA-induced convulsions is mimicked only by the o-phenylenediamine derivatives.
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Hoang-Thanh
authors.initials: HT
authors.lastname: Le
authors.forename: Irma B
authors.initials: IB
authors.lastname: Lemaire
authors.forename: Annie-Kim
authors.initials: AK
authors.lastname: Gilbert
authors.forename: François
authors.initials: F
authors.lastname: Jolicoeur
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Natacha
authors.initials: N
authors.lastname: Leduc
authors.forename: Simon
authors.initials: S
authors.lastname: Lemaire
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D010655:Phenylenediamines / Q000737:chemistry / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011506:Proteins / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D007527:Isoenzymes; D008070:Lipopolysaccharides; D010655:Phenylenediamines; D011506:Proteins; C082312:histogranin; C034193:1,2-diaminobenzene; C031000:benzimidazole; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone