TY - JOUR T1 - Histogranin-Like Antinociceptive and Anti-Inflammatory Derivatives of <em>o-</em>Phenylenediamine and Benzimidazole JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 146 LP - 155 DO - 10.1124/jpet.103.060772 VL - 309 IS - 1 AU - Hoang-Thanh Le AU - Irma B. Lemaire AU - Annie-Kim Gilbert AU - François Jolicoeur AU - Lin Yang AU - Natacha Leduc AU - Simon Lemaire Y1 - 2004/04/01 UR - http://jpet.aspetjournals.org/content/309/1/146.abstract N2 - 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 E2 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. The American Society for Pharmacology and Experimental Therapeutics ER -