Histogranin-Like Antinociceptive and Anti-Inflammatory Derivatives of o-Phenylenediamine and Benzimidazole

• Published in: The Journal of pharmacology and experimental therapeutics 2004-04, Vol.309 (1), p.146-155
• Main Authors: Le, Hoang-Thanh, Lemaire, Irma B, Gilbert, Annie-Kim, Jolicoeur, François, Yang, Lin, Leduc, Natacha, Lemaire, Simon
• Format: Article
• Language: English
• Subjects: Analgesics - therapeutic use; Animals; Anti-Inflammatory Agents - therapeutic use; Benzimidazoles - chemistry; Benzimidazoles - therapeutic use; Cyclooxygenase 2; Dinoprostone - metabolism; Disease Models, Animal; Drug Interactions; Isoenzymes - metabolism; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Pain - drug therapy; Phenylenediamines - chemistry; Phenylenediamines - therapeutic use; Prostaglandin-Endoperoxide Synthases - metabolism; Proteins - therapeutic use; Rats; Rats, Sprague-Dawley
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.060772

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-(2 R )-yl-2-( p -hydroxybenzyl)-5-carboxybenzimidazole (1) and the o -phenylenediamine derivative N -5-guanidinopentanamide-(2 S )-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 (2 R ) 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.