Anti-inflammatory effects of two new methyl and morpholine derivatives of diphenhydramine on rats

Diphenhydramines are one of the first-generation histamine H1-receptor antagonists of the ethanolamine class that demonstrate many pharmacological properties including anti-inflammatory effects. In this research, bromo (II) and two new tolyl derivatives of I, (Di [p-tolyl] [dimethylaminoethoxy] methane, III) and (Di [p-tolyl] [2-morpholinoethoxy] methane, IV) were synthesized. Their acute and chronic anti-inflammatory activities were evaluated with the formalin and histamine-induced rat paw edema. The vascular permeability in formalin and histamine-induced paw edema, in xylene-induced ear edema, and in peritonitis after acetic acid application into peritoneal cavity were also measured and compared to II. Cotton pellet-induced granuloma model was selected for inducing chronic inflammations in rats. The newly synthesized analogs of diphenhydramine seemed effective to decrease acute inflammations. It was concluded that the prominent anti-phlogistic effects of the new drugs could be related to its reduction vascular permeability mechanism(s) or to its antagonistic effects on H1 histamine receptors.

[1]  A. Mahmoudi,et al.  Synthesis and Study on Analgesic Effects of l-[l-(4-Methylphenyl) (cyclohexyl)] 4-piperidinol and l-[l-(4-Methoxyphenyl) (cyclohexyl)] 4-piperidinol as Two New Phencyclidine Derivatives , 2009, Arzneimittelforschung.

[2]  M. Triggiani,et al.  Histamine Induces Exocytosis and IL-6 Production from Human Lung Macrophages Through Interaction with H1 Receptors1 , 2001, The Journal of Immunology.

[3]  P. Fernandes,et al.  Characterization of the antinociceptive and anti-inflammatory activities of fractions obtained from Copaifera multijuga Hayne. , 2010, Journal of ethnopharmacology.

[4]  Dong-mei Chen,et al.  [Antithrombotic effects of morpholine and piperazine ring derivatives and their molecular mechanism]. , 2003, Yao xue xue bao = Acta pharmaceutica Sinica.

[5]  A. A. Miles,et al.  Vascular reactions to histamine, histamine‐liberator and leukotaxine in the skin of guinea‐pigs , 1952, The Journal of physiology.

[6]  R. Leurs,et al.  H1‐antihistamines: inverse agonism, anti‐inflammatory actions and cardiac effects , 2002, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[7]  P. Muggleton,et al.  THE ANTI‐INFLAMMATORY ACTION OF GRISEOFULVIN IN EXPERIMENTAL ANIMALS , 1960, The Journal of pharmacy and pharmacology.

[8]  K. Schiene,et al.  Antinociceptive and Antihyperalgesic Effects of Tapentadol in Animal Models of Inflammatory Pain , 2011, Journal of Pharmacology and Experimental Therapeutics.

[9]  L. Lao,et al.  Mu opioid receptor-containing neurons mediate electroacupuncture-produced anti-hyperalgesia in rats with hind paw inflammation , 2005, Brain Research.

[10]  P. Denev,et al.  Comparative investigations of the influence of H1-antihistamines on the generation of reactive oxygen species by phagocytes , 2008, Inflammation Research.

[11]  V. Demopoulos,et al.  Lipophilicity of Some Substituted Morpholine Derivatives Synthesized as Potential Antinociceptive Agents , 1990, Archiv der Pharmazie.

[12]  M. Číž,et al.  The effects of H1-antihistamines on the nitric oxide production by RAW 264.7 cells with respect to their lipophilicity. , 2009, International immunopharmacology.

[13]  P. Prathipati,et al.  Synthesis of some substituted pyrazinopyridoindoles and 3D QSAR studies along with related compounds: piperazines, piperidines, pyrazinoisoquinolines, and diphenhydramine, and its semi-rigid analogs as antihistamines (H1). , 2006, Bioorganic & medicinal chemistry.

[14]  Peter Y. Johnson,et al.  Syntheses of amine derivatives of phencyclidine , 1981 .

[15]  G. Gonzales,et al.  Diphenhydramine as an analgesic adjuvant in refractory cancer pain. , 2001, Journal of pain and symptom management.

[16]  I. Orhan,et al.  Synthesis of novel 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/-nonsubstituted benzal)hydrazone derivatives and acetylcholinesterase and butyrylcholinesterase inhibitory activities in vitro , 2011, Arzneimittelforschung.

[17]  M. Gupta,et al.  Antiinflammatory evaluation of leaves of Plumeria acuminata , 2006, BMC complementary and alternative medicine.

[18]  H. Suh,et al.  Differential cross-tolerance development between single and repeated immobilization stress on the antinociceptive effect induced by β-endorphin, 5-hydroxytryptamine, morphine, and WIN55,212-2 in the inflammatory mouse pain mode , 2011, Archives of pharmacal research.

[19]  Cathryn A Valancius,et al.  Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models. , 2005, European journal of pharmacology.

[20]  J. McDougall,et al.  Attenuation of knee joint inflammation by peripherally administered endomorphin-1 , 2007, Journal of Molecular Neuroscience.

[21]  F. Simons,et al.  H1-Antihistamines: more relevant than ever in the treatment of allergic disorders. , 2003, The Journal of allergy and clinical immunology.

[22]  J. Flório,et al.  Maternal exposure to diphenhydramine during the fetal period in rats: effects on physical and neurobehavioral development and on neurochemical parameters. , 2004, Neurotoxicology and teratology.

[23]  G. Primofiore,et al.  1-substituted 2-benzylaminobenzimidazole derivatives: compounds with H1-antihistaminic activity , 1992 .

[24]  C A WINTER,et al.  Carrageenin-Induced Edema in Hind Paw of the Rat as an Assay for Antiinflammatory Drugs , 1962, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[25]  F. Simons,et al.  The pharmacology and use of H1-receptor-antagonist drugs. , 1994, The New England journal of medicine.

[26]  R. Seifert,et al.  Receptor-independent G protein activation may account for the stimulatory effects of first-generation H1-receptor antagonists in HL-60 cells, basophils, and mast cells. , 1996, Biochemical pharmacology.

[27]  Leila Barghi,et al.  Synthesis and determination of acute and chronic pain activities of 1-[1-(3-methylphenyl) (tetralyl)]piperidine as a new derivative of phencyclidine via tail immersion and formalin tests , 2010, Arzneimittelforschung.