title: Antiinflammatory and analgesic activity of a non-peptide substance P receptor antagonist.
abstract: CP-96,345, a potent non-peptide antagonist of the substance P (SP) receptor, inhibited SP-, neurokinin A (NKA)- and neurokinin B-induced plasma extravasation in guinea pig dorsal skin. The inhibition was specific for the three tachykinins; CP-96,345 was not active against plasma leakage caused by histamine, bradykinin, platelet-activating factor or leukotriene D4. CP-96,345 inhibited capsaicin-induced plasma extravasation in the ureter, an inflammatory response caused by neuropeptides released from afferent C-fibers. Thus, the NK1 receptor appears to play a major role in vascular permeability increases induced by exogenous and endogenous tachykinins. In contrast, CP-96,345 was inactive against SP- and NKA-induced contraction of guinea pig ureter, suggesting that the smooth muscle contraction is not NK1-mediated. CP-96,345 exhibited analgesic activity in acetic acid-induced abdominal stretching in mice, indicating for the first time that SP plays a critical role in this model. The results of these studies support a pathophysiological role of SP and NK1 receptor under acute neurogenic inflammatory conditions and in pain.
authors.affiliation: Department of Medicinal Biology, Central Research Division, Pfizer Inc., Aichi, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nagahisa
authors.forename: Y
authors.initials: Y
authors.lastname: Kanai
authors.forename: O
authors.initials: O
authors.lastname: Suga
authors.forename: K
authors.initials: K
authors.lastname: Taniguchi
authors.forename: M
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: J A
authors.initials: JA
authors.lastname: Lowe
authors.forename: H J
authors.initials: HJ
authors.lastname: Hess
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010972:Platelet Activating Factor / Q000494:pharmacology; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013189:SRS-A / Q000494:pharmacology; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D015320:Tachykinins / Q000494:pharmacology; D014513:Ureter / Q000187:drug effects
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D010972:Platelet Activating Factor; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D013189:SRS-A; D015320:Tachykinins; D006632:Histamine; D002211:Capsaicin; D001920:Bradykinin; C066892:CP 96345