ReN 1869, a novel tricyclic antihistamine, is active against neurogenic pain and inflammation.
The tricyclic compound (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid (ReN 1869) is a novel, selective histamine H(1) receptor antagonist. It is orally available, well tolerated, easily enters the central nervous system (CNS) but no adverse effects are seen in mice at 300 mg/kg. ReN 1869 at 0.01-10 mg/kg is antinociceptive in tests of chemical nociception in rodents (formalin, capsaicin, phenyl quinone writhing) but not in thermal tests (hot plate and tail flick). ReN 1869 amplifies the analgesic action of morphine but does not show tolerance after chronic dosing. Moreover, the compound is effective against inflammation of neurogenic origin (antidromic nerve stimulation, histamine-evoked edema) but not in carrageenan-induced inflammation. We suggest that ReN 1869, via H(1) blockade, counteracts the effect of histamine liberated from activated mast cells and inhibits pain transmission in the dorsal spinal cord. ReN 1869 represents a new class of antihistamines with pain-relieving properties that probably is mediated centrally through histamine H(1) receptors but alternative mechanisms of action cannot be excluded.
Olsen
Uffe B
UB
Department of General Pharmacology, Novo Nordisk A/S, 2760 Maaloev, Denmark.
Eltorp
Christina T
CT
Ingvardsen
Bente K
BK
Jørgensen
Tine K
TK
Lundbaek
Jens A
JA
Thomsen
Christian
C
Hansen
Anker J
AJ
D000818:Animals; D016227:Benzoquinones; D001665:Binding Sites; D016466:CHO Cells; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002351:Carrageenan; D002490:Central Nervous System / Q000187:drug effects; D006224:Cricetinae; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005119:Extravasation of Diagnostic and Therapeutic Materials; D015870:Gene Expression / Q000187:drug effects; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000627:therapeutic use*; D066298:In Vitro Techniques; D051379:Mice; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D010880:Piperidines / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014316:Tritium
D016227:Benzoquinones; D015220:Calcium Channels; D006634:Histamine H1 Antagonists; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; C450800:ReN 1869; D011969:Receptors, Histamine H1; D014316:Tritium; C029322:phenylbenzoquinone; D006632:Histamine; D002351:Carrageenan; D011738:Pyrilamine; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D002118:Calcium