title: 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.affiliation: Platelet Department, Sandoz Research Institute, East Hanover, New Jersey.
authors.forename: D A
authors.initials: DA
authors.lastname: Handley
authors.forename: R G
authors.initials: RG
authors.lastname: Van Valen
authors.forename: M K
authors.initials: MK
authors.lastname: Melden
authors.forename: W J
authors.initials: WJ
authors.lastname: Houlihan
authors.forename: R N
authors.initials: RN
authors.lastname: Saunders
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects; D002428:Cebus; D003094:Collagen / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D006168:Guinea Pigs; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats
chemical_list: D007546:Isoquinolines; D010972:Platelet Activating Factor; C057722:SDZ 64-412; D000244:Adenosine Diphosphate; D003094:Collagen; D004837:Epinephrine