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 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.
Footnotes
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This work was supported by the Canadian Institutes of Health Research and University Medical Discoveries Inc.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.060772.
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ABBREVIATIONS: HN, histogranin; NMDA, N-methyl-d-aspartate; CFA, complete Freund's adjuvant; MBHA, methylbenzhydrylamine; RP-HPLC, reversed phase-high-performance liquid chromatography; PyBOP, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate; NMP, 1-methyl-2-pyrrolidone; Boc, t-butyloxycarbonyl; HF, hydrogen fluoride; AD50, the concentration that produces 50% analgesia; PGE2, prostaglandin E2; COX, cyclooxygenase; TBS-T, Tris-buffered saline/0.1% Tween 20; LPS, lipopolysaccharide; [(2S,3R)TMT1]DPDPE, [(2S,3R)β-methyl-2′,6′-dimethyltyrosine1][d-Pen1,d-Pen5]-enkephalin; CGP-39653, d,l-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid.
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↵1 Current address: Département de psychiatrie, Centre Universitaire de Santé de l'Estrie, 3001, 12 ième Avenue Nord, Fleurimont, QC, Canada J1H 5M4.
- Received October 1, 2003.
- Accepted December 8, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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