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: Hoang-Thanh Le, Irma B Lemaire, Annie-Kim Gilbert, François Jolicoeur, Lin Yang, Natacha Leduc, Simon Lemaire
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 309 Issue 1 Pg. 146-55 (Apr 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14718586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Anti-Inflammatory Agents
• Benzimidazoles
• Isoenzymes
• Lipopolysaccharides
• Phenylenediamines
• Proteins
• histogranin
• 1,2-diaminobenzene
• benzimidazole
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone

Topics

• Analgesics (therapeutic use)
• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Benzimidazoles (chemistry, therapeutic use)
• Cyclooxygenase 2
• Dinoprostone (metabolism)
• Disease Models, Animal
• Drug Interactions
• Isoenzymes (metabolism)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Pain (drug therapy)
• Phenylenediamines (chemistry, therapeutic use)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Proteins (therapeutic use)
• Rats
• Rats, Sprague-Dawley