Sch 37370: a potent, orally active, dual antagonist of platelet-activating factor and histamine.

Abstract

Platelet-activating factor (PAF) and histamine are potent bronchospastic agents and possess additional properties such as induction of vasopermeability and activation of inflammatory cells that are consistent with their ability to mediate allergic and inflammatory responses. From a structural series with anticipated antihistamine activity, Sch 37370 (1-acetyl-4(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2- b]pyridine-11-ylidine)piperidine) has been identified as a dual antagonist of PAF and histamine in vitro and in vivo and has been compared with several selective antagonists of PAF and histamine. Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM). Sch 37370 blocks the binding of [3H]pyrilamine to histamine-H1 receptors in rat brain membranes. Administered i.v. to guinea pigs, Sch 37370 is an equipotent antagonist of PAF and histamine-induced bronchospasm (ED50 = 0.6-0.7 mg/kg). Orally in guinea pigs, Sch 37370 is somewhat more effective against bronchospasms to histamine (ED50 = 2.4 mg/kg) than against PAF (ED50 = 4.1-6.0 mg/kg) or serotonin (ED50 = 9.6 mg/kg). Sch 37370 only weakly antagonizes methacholine-induced bronchospasm (ED50 = 51 mg/kg) and is completely inactive at 50 mg/kg against leukotriene C4 or substance P. Sch 37370 blocks hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or histamine, as well as PAF-induced lethality in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: M M Billah, R W Chapman, R W Egan, H Gilchrest, J J Piwinski, J Sherwood, M I Siegel, R E West Jr, W Kreutner
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 252 Issue 3 Pg. 1090-6 (Mar 1990) ISSN: 0022-3565 [Print] United States
• PMID: 2319461 (Publication Type: Journal Article)

Chemical References

• Histamine Antagonists
• Piperidines
• Platelet Activating Factor
• Loratadine
• Histamine
• N-acetyldesloratadine
• Pyrilamine

Topics

• Administration, Oral
• Animals
• Binding, Competitive
• Brain (drug effects, metabolism)
• Bronchial Spasm (drug therapy)
• Female
• Guinea Pigs
• Histamine (metabolism)
• Histamine Antagonists (administration & dosage, pharmacology, therapeutic use)
• Humans
• Loratadine (analogs & derivatives)
• Lung (drug effects, metabolism)
• Macaca fascicularis
• Male
• Mice
• Piperidines (administration & dosage, pharmacology, therapeutic use)
• Platelet Activating Factor (antagonists & inhibitors, metabolism)
• Platelet Aggregation (drug effects)
• Pyrilamine (antagonists & inhibitors, metabolism)
• Rats