3-5-dimethyl-2-(3-pyridyl)thiazolidin-4-one and Anaphylaxis

SM-12502 ((+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl, CAS 119383-00-5) inhibited platelet-activating factor (PAF)-induced aggregation of rabbit and human platelets with IC50 values of 2.3 mumol/l and 4.7 mumol/l, respectively, but did not inhibit platelet aggregation induced by adenosine diphosphate, collagen, thrombin, arachidonic acid, U46619 (a thromboxane A2 agonist) or Ca2+ ionophore A23187 at concentrations up to 400 mumol/l. SM-12502 competitively antagonized 3H-PAF binding to rabbit platelets with an IC50 of 1.0 mumol/l. In contrast, the anti-PAF activity of the optical isomer SM-12501 ((-)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl) was much weaker and its IC50 was more than 100 mumol/l. SM-12502 prevented PAF-induced death in mice with ID50 values of 4.8 mg/kg (i.v.) or 68.6 mg/kg (p.o.). In guinea pigs, SM-12502 inhibited PAF (0.1 micrograms/kg)-induced hemoconcentration with ID50 values of 1.9 mg/kg (i.v.) or 40.2 mg/kg (p.o.). In addition, SM-12502 inhibited PAF (10 ng/kg)-induced hypotension in rats with ID50 values of 2.0 mg/kg (i.v.) or 6.5 mg/kg (p.o.). The in vivo effects of SM-12501 were much weaker. Orally administered SM-12502 showed rapid absorption and a long duration of pharmacological activity in rats. SM-12502 afforded dose-dependent protection against anaphylactic death in mice with ID50 values of 18.4 mg/kg (i.v.) and 136 mg/kg (p.o.). It also inhibited endotoxin (E. coli 0.55:B5, 60 mg/kg)-induced death in mice, with ID50 values of 119 mg/kg (i.v.) and 182 mg/kg (p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anaphylaxis; Animals; Blood Platelets; Blood Pressure; Endotoxins; Guinea Pigs; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Platelet Activating Factor; Platelet Aggregation; Platelet Membrane Glycoproteins; Rabbits; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Stereoisomerism; Thiazoles; Thiazolidines

1. To investigate the role of platelet activating factor (PAF) in the immediate asthmatic response, we examined the bronchial reactivity to histamine after administration of PAF to guinea-pigs or antigen challenge to passively sensitized guinea-pigs. 2. A bolus injection of PAF (20-40 ng kg-1), which did not cause a significant increase in intrathoracic pressure (ITP), augmented the bronchial response to histamine almost 8 fold. This airway hyperreactivity was observed even 1 min after PAF treatment. 3. A subthreshold dose of antigen (0.01 mg kg-1, i.v.) also provoked hyperreactivity to histamine, which became significant 6 and 11 min after the antigen treatment. 4. The specific PAF-antagonists, SM-10661 and CV-6209 (i.v.) dose-dependently inhibited both PAF- and antigen-induced airway hyperreactivities to histamine. 5. These results suggest that PAF plays an important role in antigen-induced acute airway responses by augmenting the activities of spasmogens.

Topics: Anaphylaxis; Animals; Asthma; Bronchi; Guinea Pigs; Histamine; Male; Ovalbumin; Platelet Activating Factor; Platelet Count; Pyridinium Compounds; Respiratory Function Tests; SRS-A; Thiazoles; Thiazolidines

The effect of SM-10661, a selective antagonist of platelet-activating factor (PAF), on passive anaphylactic bronchoconstriction was examined in guinea pigs. A challenge of ovalbumin to passively sensitized guinea pigs induced bronchoconstriction, which peaked at 4 min. When SM-10661 was administered intravenously 2 min before ovalbumin challenge, bronchoconstriction was inhibited dose-dependently with an ID50 of 68 mg/kg. In guinea pigs pretreated with 15 micrograms/kg mepyramine which is a suboptimal dose, antigen-induced bronchoconstriction peaked at 4-6 min, but was inhibited by SM-10661 with an ID50 of 21 mg/kg. When guinea pigs were pretreated intravenously with 2.5 mg/kg mepyramine, 1 mg/kg indomethacin and 0.01 mg/kg propranolol, the antigen-induced bronchoconstriction peaked at 6 min. SM-10661 inhibited the response with an ID50 of 45 mg/kg. Histamine- and leukotriene D4-induced bronchoconstrictions were unaffected by up to 100 mg/kg SM-10661. Ovalbumin challenge of minced lungs from passively sensitized guinea pigs triggered the release of leukotrienes and histamine. SM-10661 had no effect on the antigen-induced release of peptide leukotrienes or histamine up to 10(-4) M. These results indicate that SM-10661 may be a useful tool to investigate the role of PAF in antigen-induced anaphylactic bronchoconstriction.

Topics: Anaphylaxis; Animals; Asthma; Bronchoconstriction; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Indomethacin; Male; Ovalbumin; Platelet Activating Factor; Propranolol; Pyrilamine; SRS-A; Thiazoles; Thiazolidines