Biological effects of the orally active platelet activating factor receptor antagonist SDZ 64-412.

Abstract

SDZ 64-412 is a trimethoxyphenylethylphenyl imidazo[2,1-a] isoquinoline molecule that displays marked in vitro inhibition of platelet activating factor (PAF)-induced human platelet aggregation (IC50 = 60 nM) but is without inhibition (at 100 microM) of epinephrine-, ADP- or collagen-induced aggregation. SDZ 64-412 antagonized receptor binding of radiolabeled PAF to human platelet membranes with an IC50 = 60 nM. In the rat, SDZ 64-412 inhibited 100 ng kg-1 PAF-induced hypotension when given i.v. (ED50 = 0.23 mg kg-1) or p.o. (ED50 = 13 mg kg-1). In the guinea pig, SDZ 64-412 inhibited 50 ng kg-1 PAF-induced bronchoconstriction (ED50 = 4.2 mg kg-1 p.o.) and hemoconcentration (ED50 = 5.0 mg kg-1 p.o.). SDZ 64-412 exhibited oral activity in the dog against 1.5 micrograms kg-1 PAF-induced hypotension (ED50 = 5.1 mg kg-1 p.o.) and hemoconcentration (ED50 = 4.9 mg kg-1) and 3.5 micrograms kg-1 PAF-induced hemoconcentration in the cebus primate (ED50 = 12.8 mg kg-1 p.o.). SDZ 64-412 protected in a dose-dependent manner against PAF-induced lethality (LD75 = 75 micrograms kg-1 i.v.) in mice, where 20 mg kg-1 p.o. improved survival from 25 +/- 4% to 77 +/- 8%. SDZ 64-412 afforded complete protection against endotoxin-induced lethality (LD90 = 7.5 mg kg-1 endotoxin i.v.) where the ED50 was 45 mg kg-1 twice predose.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: D A Handley, R G Van Valen, M K Melden, W J Houlihan, R N Saunders
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 247 Issue 2 Pg. 617-23 (Nov 1988) ISSN: 0022-3565 [Print] United States
• PMID: 3183958 (Publication Type: Journal Article)

Chemical References

• Isoquinolines
• Platelet Activating Factor
• SDZ 64-412
• Adenosine Diphosphate
• Collagen
• Epinephrine

Topics

• Adenosine Diphosphate (pharmacology)
• Animals
• Blood Pressure (drug effects)
• Bronchi (drug effects)
• Cebus
• Collagen (pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Epinephrine (pharmacology)
• Guinea Pigs
• Isoquinolines (pharmacology)
• Mice
• Platelet Activating Factor (antagonists & inhibitors)
• Platelet Aggregation (drug effects)
• Rats