ABSTRACT
A series of new tropan derivatives have been synthesized and investigated, which can both weaken and potentiate the serotonin-induced cerebrovascular constrictory reactions. The compound LK-728 produces a pronounced antiserotonin cerebrovascular action comparable to that of tropoxin, but being superior to the reference drug in the effect duration. On the contrary, another tropan derivative LK-769 enhances the cerebrovascular response to serotonin. A similar effect was demonstrated with the well-known antimigraine agent sumatriptan, which is an agonist of 5HT1B/1D receptors. The ability of sumatriptan to increase the local cerebral blood flow which was observed in our experiments, may also play an important role in the mechanism of the antimigraine action produced by this serotonin receptor agonist.
Subject(s)
Cerebrovascular Circulation/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Serotonin/metabolism , Tropanes/pharmacology , Vasoconstrictor Agents/pharmacology , Animals , Aza Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Male , Rats , Serotonin 5-HT1 Receptor Agonists , Serotonin 5-HT2 Receptor Antagonists , Sumatriptan/pharmacology , Tryptamines/pharmacology , Tryptamines/therapeutic useABSTRACT
The effects of the antimigraine drug tropoxin and its main molecular fragments - tropan and 3,4,5-trimetoxybenzoate (TMB) - on the serotonin sensitivity of postsynaptic neuronal membrane in rat brain sensorimotor area has been studied using a microionophoretic (MIP) technique. All the three substances significantly reduce the excitatory neuronal response to serotonin, which is manifested by an increase in the rate of the spontaneous action potentials. With respect to the antiserotonin effect, the substances can be arranged in the following order: tropoxin > tropan > TMB. The sum of the effects of tropan and TMB (for both simultaneous and separate action upon the target cells) was significantly lower than the effect of tropoxin in all doses (MIP currents). It is concluded that a pronounced antiserotonin effect of tropoxin is produced only provided that the entire molecular configuration is retained. Tropan and TMB, being tropoxin metabolites, are probably capable of prolonging the antimigraine action upon the decay of tropoxin in the organism. A relationship between the structure and action of serotonin receptor blockers of the tropan series is discussed.
Subject(s)
Aza Compounds/metabolism , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Cerebral Cortex/metabolism , Neurons/metabolism , Receptors, Serotonin/metabolism , Serotonin Antagonists/metabolism , Animals , Aza Compounds/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Dose-Response Relationship, Drug , Male , Migraine Disorders/drug therapy , Protein Binding , Rats , Serotonin Antagonists/administration & dosage , Structure-Activity RelationshipABSTRACT
The effect of the new antimigraine drug tropoxin - the serotonin receptor (5-HT2) antagonist - on the human platelet aggregation in vitro induced by ADP (1 x 10(-5) M) and epinephrine (2.5 x 10(-6) M) was studied. Tropoxin reliably inhibited the ADP-induced platelet aggregation in a concentration range of 0.01 - 7 mg/ml. A significant inhibition effect with respect to the epinephrine-induced platelet aggregation was observed in a drug concentration range of 2 - 7 mg/ml, although a reliable antiaggregant activity was also observed below 2 mg/ml. A bolus administration of tropoxin (10 mg/kg) in rabbits decreased the ADP-induced platelet aggregation ex vivo by a factor of 1.2 - 1.4. The effect appeared 45 min after treatment and was observed during subsequent 30 min.
